Comprehensive statistical analysis of the pharmacokinetics, safety and clinical benefit rate of MitoTam in a single-center phase I/Ib trial in patients with metastatic solid tumors

Comprehensive statistical analysis of the pharmacokinetics, safety and clinical benefit rate of MitoTam in a single-center phase I/Ib trial in patients with metastatic solid tumors | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comprehensive statistical analysis of the pharmacokinetics, safety and clinical benefit rate of MitoTam in a single-center phase I/Ib trial in patients with metastatic solid tumors Olga Bartosova, Zuzana Bielcikova, Jan Stursa, Michal Pesta, Jiri Neuzil, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4669827/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background MitoTam, the first mitochondrial inhibitor to disrupt complex I (CI)-dependent respiration, previously showed antitumor activity against renal cell carcinoma (RCC) with a good safety profile. We investigated the relationships of pharmacokinetic (PK) parameters, biodistribution, and patient baseline diagnosis with the clinical outcome and toxicity of MitoTam. Methods In the phase I/Ib MitoTam-01 trial, patients with metastatic solid tumors were treated with MitoTam monotherapy. PK parameters were calculated separately for the doses used in both trial phases. Data were analyzed descriptive analyses and using the generalized linear model framework as stochastic test. Results The non-compartmental analysis of PK parameters showed that the extent of exposure was positively correlated with the dose. Most of the PK profiles suggested that MitoTam was redistributed from the tissues or from protein binding back into the blood circulation, with very low accumulation. The exposure‒efficacy relationship did not show significant differences between responders and non-responders in phase Ib. However, the AUC 0-t and C max values were greater in RCC patients than in responders with other diagnoses. These data are consistent with the preclinical findings showing preferential MitoTam accumulation in kidneys and the high clinical benefit rate in RCC patients in the phase Ib part. Conclusion These comprehensive analyses demonstrate the impact of MitoTam on the clinical benefit rate that is related to the dose and corresponding PK parameters, as well the underlying diagnosis. The PK data supported the previously recommended dose of 3.0 mg/kg weekly for future trials. Registration: EudraCT 2017-004441-25 (November 1, 2017) MitoTam pharmacokinetics phase I/Ib clinical benefit rate safety renal cell carcinoma Introduction Many mitochondrial pathways, including oxidative phosphorylation (OXPHOS), fatty acid, glutamine, and one-carbon metabolism, are altered in tumors due to mutations in oncogenes, tumor suppressor genes, and metabolic enzymes [ 1 ]. Mitocans are anticancer agents that act via targets on or within mitochondria. However, their translation from preclinical experiments has been challenging, and only a few compounds have entered early-stage clinical trials [ 1 ]. To date, only one mitochondria-targeting agent (venetoclax) has been approved for chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) [ 2 ]. Negative outcomes of several clinical trials [ 1 , 3 – 5 ] were critically assessed and generalized to the entire research concerning mitochondrial targeting [ 6 ]. Our research shows that targeting mitochondria is a plausible anticancer therapeutic strategy. Mitochondrially targeted tamoxifen (MitoTam) is a triphenylphosphonium (TPP + )-tagged mitocan that interferes with mitochondrial functions and complex I (CI)-dependent respiration [ 7 ]. By ‘intercalating’ into the inner mitochondrial membrane, MitoTam dissipates the mitochondrial membrane potential, promoting both apoptosis and necroptosis [ 8 ]. The anticancer effect of MitoTam against renal cell carcinoma (RCC) was as efficient as immunotherapy with immune checkpoint inhibitors in an animal model [ 8 ]. The clinical efficacy and safety of MitoTam were evaluated in the phase I/Ib MitoTam-01 trial. 9 We reported a clinical benefit rate (CBR) of MitoTam of 37% (14/38) in patients with metastatic solid tumors, regardless of the diagnosis, and of 83% (5/6) among patients with RCC enrolled in the phase Ib part. All patients except one with CBR achieved disease stabilization following MitoTam treatment, as measured by RECIST 1.1 criteria. The maximum tolerated dose was 5.0 mg/kg, the penultimate dose in the series of nine doses tested. Systemic toxicities were mainly hematological adverse events (AEs) and fever. Local toxicities were related to the administration route, including risk of thromboembolic (TE) complications. The pharmacokinetic (PK) analysis was a primary endpoint of the MitoTam-01 trial to determine the total exposure, optimal dosing frequency, and potential accumulation of MitoTam. The initial routine PK analysis [ 9 ], performed by an external evaluator, led us to more detailed and accurate assessment of results. In this article, we report a comprehensive and amended exploration of MitoTam PK, including the identification of parameters that may improve the odds of a clinical benefit or influence its toxicity. Herein, we also evaluated marginal PK parameters to obtain more insightful results. To obtain more robust data on the safety and efficacy of MitoTam, the original elimination half-life [ 9 ] was re-evaluated in this publication as distribution serum half-life (T½α) and terminal serum elimination half-life (T½β). We also report correlations between the CBR and PK parameters, including a critical assessment of their reliability, focusing on treatment regimens, number of treatment cycles, dose, sex, baseline diagnosis, and histogenetic origin of the disease. Patients and methods Study design MitoTam-01 was an open-label, single-arm, non-randomized, single center phase I/Ib trial that evaluated the safety and efficacy of MitoTam. The study design was previously reported (EudraCT 2017-004441-25; registration date: November 1, 2017) [ 9 ]. All patients had previously undergone systemic anticancer therapy (three in median) that had been terminated. The ClinPK reporting checklist was consulted in the preparation of this report [ 10 ]. The phase I study evaluated the safety of a single cycle of MitoTam across nine escalating doses and two treatment schemas. Phase Ib evaluated the efficacy and safety of repeated doses of MitoTam in three different regimens. Supplemental Tables S1–S7 present further information about the study design, including dosing and treatment schemes, administration of MitoTam, prohibited medications, and timing of blood sampling. MitoTam analysis The analysis of MitoTam and the internal standard (IS) MitoTam-D15 are described in detail in the Supplemental Methods. Determination of PK parameters Phoenix WinNonlin® software version 8.1 (Certara, USA) was used to calculate the PK parameters. Non-compartmental modeling used the linear trapezoidal/linear interpolation calculation methods. The best-fit method with uniform weighting was used to calculate the terminal elimination rate constant distribution and elimination half-life. Serum concentrations below the lower limit of quantification were set to zero. The following PK parameters were estimated for each subject, sampling day, and cycle: maximum serum concentration (C max ), area under the serum concentration curve (AUC 0‒ t ), time to reach the maximum serum concentration (T max ), distribution serum half-life (T ½ α), terminal serum elimination half-life (T ½ β), mean residence time (MRT), serum clearance (CL), volume of distribution (V z ), and accumulation index. Analysis of PK variance was used to test the effects of phase, cohort, cycle, day, and sex at a 5% significance level for AUC 0 − t and C max . PK parameters requiring extrapolation of the elimination phase to infinity (T ½ α, T ½ β, MRT, and CL) were not considered as the main parameters in statistical correlation analysis. These extrapolated PK parameters should be evaluated cautiously. Statistical analysis Descriptive statistics, including the empirical mean, standard deviation (SD), empirical median, minimum, first quartile (i.e., 25th percentile), empirical median, third quartile (i.e., 75th percentile), and maximum, were calculated for the key variables. These parameters are also presented as matrices in pairwise plots. Where appropriate we used random effects mixed models (generalized linear mixed models [GLMM]) in addition to the descriptive PK analysis. The theoretical test level was set to 0.05. Results with p values of < 0.05 were considered statistically significant and reported as such in this manuscript. R statistical software by R Core Team (2021) version 4.1.1 (released on August 10, 2021) was used [ 11 ]. All of the stochastic model formulations together with the estimates of the statistically significant model parameters and corresponding p-values are given in Appendix A. Results Patient characteristics Seventy-five patients were enrolled between May 23, 2018, and July 22, 2020, comprising 37 in phase I and 38 in phase Ib. Their characteristics are summarized in Table 1 and Supplemental Tables S8 and S9. We found no significant differences in the baseline characteristics among treatment groups that could be relevant to the exposure, distribution, metabolism, or clearance of MitoTam that might influence its PK. Table 1 Demographic data of enrolled patients (N = 75) Dose of MitoTam, mg/kg (n) Age, years, mean (SD) Sex (M/F) Height, cm, mean (SD) Weight, kg, mean (SD) BMI, kg/m 2 , mean (SD) Phase I 0.25 (4) 59.75 (9.36) 2/2 172.75 (9.91) 72.67 (16.05) 24.61 (2.59) 0.5 (6) 50.67 (8.84) 2/4 167.00 (7.66) 69.83 (19.19) 24.85 (5.87) 1.0 (3) 47.33 (3.30) 2/1 166.67 (13.82) 83.67 (4.19) 30.55 (3.96) 1.5 (3) 59.67 (5.44) 2/1 172.00 (10.71) 106.33 (13.57) 36.66 (8.35) 2.25 (6) 62.17 (8.32) 2/4 167.00 (8.91) 78.20 (13.78) 28.03 (3.93) 3.0 (5) 61.40 (6.80) 2/3 169.80 (11.57) 83.60 (17.00) 29.22 (6.74) 4.0 (3) 65.33 (8.06) 1/2 165.33 (5.91) 66.33 (6.65) 24.46 (3.78) 5.0 (6) 66.50 (3.59) 4/2 172.67 (8.73) 83.83 (17.18) 27.79 (3.72) 6.0 (1) 68.00 (0.00) 1/0 180.00 (0.00) 87.00 (0.00) 26.85 (0.00) Phase Ib 1.0 (20) 59.05 (9.66) 12/8 172.35 (9.71) 77.16 (18.37) 26.25 (5.10) 3.0 (9) 63.78 (8.69) 5/4 167.67 (8.62) 79.11 (17.85) 28.06 (5.77) 4.0 (9) 63.56 (5.54) 6/3 176.22 (8.40) 83.89 (13.15) 27.01 (3.95) SD standard deviation, M males, F females, BMI body mass index Pharmacokinetics Serial PK data were analyzed for three-times-weekly (t.i.w.; n = 27) and once-weekly (q.w.; n = 10) dosing schemes in phase I, and in phase Ib (n = 20 vs. n = 18). Table 2 shows The PK parameters for the nine cohorts in phase I (0.25‒6.0 mg/kg) and three in phase Ib (1.0, 3.0, and 4.0 mg/kg). Table 2 Pharmacokinetic parameters of MitoTam for all cohorts and regimens in phases I and Ib Phase I, cohort 0.25 mg/kg (n = 4) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 960.81 740.59 499.20 280.00 1720.00 1440.00 C max [ng/mL] 302.70 223.46 304.50 133.50 385.00 251.50 T max [h] 0.43 0.43 0.50 0.08 0.5 0.42 T ½ α [h] 1.41 2.07 0.55 0.40 1.45 1.05 CL [mL/h/kg] 412.08 314.56 299.55 136.43 725.37 588.95 V z [mL/kg] 7315.35 7843.77 3527.90 2919.73 11 661.85 8742.13 Accumulation index 1.16 0.22 1.08 1.00 1.29 0.29 Phase I, cohort 0.5 mg/kg (n = 6) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 4447.31 7805.87 1495.40 979.10 2148.90 1169.80 C max [ng/mL] 1037.80 1523.36 500.00 229.00 764.00 535.00 T max [h] 0.11 0.10 0.083 0.083 0.083 0 T ½ α [h] 1.26 0.72 0.90 0.70 2.00 1.30 CL [mL/h/kg] 265.91 167.58 271.10 127.70 404.65 276.95 V z [mL/kg] 11 023.61 8281.26 10 019.00 6713.15 13 545.78 6832.63 Accumulation index 1.51 0.34 1.43 1.20 1.75 0.55 Phase I, cohort 1.0 mg/kg (n = 3) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 3068.52 1535.63 2160.3 1925.15 4405.6 2480.45 C max [ng/mL] 1019.11 772.26 669.00 469.50 1565.00 1095.50 T max [h] 0.27 0.21 0.08 0.08 0.5 0.42 T ½ α [h] 0.81 0.43 0.60 0.40 1.30 0.90 CL [mL/h/kg] 342.28 123.22 403.50 186.10 447.58 261.48 V z [mL/kg] 9588.68 5745.49 8293.80 4887.75 14 132.03 9244.28 Accumulation index 1.21 0.16 1.21 1.07 1.30 0.22 Phase I, cohort 1.5 mg/kg (n = 3) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 14 595.87 24 224.16 3925.00 3115.80 15 371.30 12 255.50 C max [ng/mL] 2486.55 2424.98 1530.00 723.00 4180.00 3457.00 T max [h] 1.70 3.72 0.08 0.08 1.75 1.67 T ½ α [h] 1.32 1.98 0.34 0.24 1.62 1.37 CL [mL/h/kg] 379.08 221.00 356.00 177.95 591.75 413.80 V z [mL/kg] 9975.18 6374.44 10 149.30 3601.50 16 261.80 12 660.30 Accumulation index 1.17 0.10 1.20 1.06 1.27 0.21 Phase I, cohort 2.25 mg/kg (n = 6) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 22 250 17 553.87 13 461.75 8242.00 37 726.73 29 484.73 C max [ng/mL] 2734.68 1509.56 2435.00 1547.50 3450.00 1902.50 T max [h] 1.74 3.25 0.50 0.08 0.50 0.42 T ½ α [h] 1.17 0.77 1.04 0.68 1.65 0.97 CL [mL/h/kg] 171.81 160.47 111.20 51.55 316.2 264.65 V z [mL/kg] 5347.69 6527.47 2174.9 1357.55 8769.35 7411.80 Accumulation index 1.22 0.16 1.19 1.08 1.35 0.27 Phase I, cohort 3.0 mg/kg (n = 5) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 23 783.81 17 643.06 14 704.70 12 005.55 39 495.65 27 490.10 C max [ng/mL] 4204.00 3739.03 3040.00 1867.50 5035.00 3167.50 T max [h] 0.33 0.12 0.25 0.25 0.50 0.25 T ½ α [h] 1.89 1.45 1.38 0.94 2.50 1.56 CL [mL/h/kg] 177.22 109.53 225.4 50.5 279.85 229.35 V z [mL/kg] 4384.36 2887.41 5406.80 1000.05 7257.45 6257.40 Accumulation index 1.14 0.08 1.15 1.06 1.20 0.14 Phase I, cohort 4.0 mg/kg (n = 3) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 27 421.30 2487.66 28 932.00 23 914.40 29 417.50 5503.10 C max [ng/mL] 3311.67 824.04 2980.00 2510.00 4445.00 1935.00 T max [h] 0.33 0.12 0.25 0.25 0.50 0.25 T ½ α [h] 1.86 0.32 1.93 1.45 2.22 0.77 CL [mL/h/kg] 141.43 13.55 132.10 131.60 160.60 29.00 V z [mL/kg] 9135.16 1612.07 8434.60 7606.60 11 364.30 3757.70 Accumulation index x x x x x x Phase I, cohort 5.0 mg/kg (n = 6) Mean SD Median Q1 Q3 IQR AUC 0−t [ng*h/mL] 47 833.12 36 209.78 36 341.20 21 513.58 66 428.85 44 915.28 C max [ng/mL] 6395.00 3772.63 6100.00 2670.00 10 067.50 7397.50 T max [h] 1.25 2.13 0.25 0.25 1.88 1.63 T ½ α [h] 10.82 17.37 1.70 0.33 21.53 21.20 CL [mL/h/kg] 142.52 65.56 133.15 87.30 216.6 129.30 V z [mL/kg] 9858.40 6127.42 7716.75 4221.05 17 917.28 13 696.23 Accumulation index x x x x x x Phase I, cohort 6.0 mg/kg (n = 1) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 119 682.50 0 119 682.50 59 841.25 59 841.25 0 C max [ng/mL] 15 800 0 15 800 7900 7900 0 T max [h] 0.25 0 0.25 0.125 0.125 0 T ½ α [h] 5.39 0 5.39 2.70 2.70 0 CL [mL/h/kg] 49.7 0 49.7 24.85 24.85 0 V z [mL/kg] 1964.3 0 1964.3 982.15 982.15 0 Accumulation index x x x x x x Phase Ib, regimen 1: 1.0 mg/kg (n = 20) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 34 891.56 30 941.63 28 427.90 9929.95 49 214.08 39 284.13 C max [ng/mL] 4461.43 3497.12 3670.00 2116.25 6300 4183.75 T max [h] 0.42 0.34 0.25 0.25 0.50 0.25 T ½ α [h] 1.56 6.04 0.40 0.31 0.63 0.32 CL [mL/h/kg] 69.37 105.89 21.55 12.35 62.23 49.88 V z [mL/kg] 2325.08 2467.06 1319.75 892.95 2813.28 1920.33 Accumulation index 2.34 3.37 1.61 1.14 2.15 1.01 Phase Ib, regimen 2: 3.0 mg/kg (n = 9) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 38 181.86 28 141.25 29 585.50 15 334.95 53 474.25 38 139.30 C max [ng/mL] 5483.00 2991.03 4800.00 2860.00 7302.50 4442.50 T max [h] 0.67 1.64 0.50 0.25 0.50 0.25 T ½ α [h] 1.28 2.43 0.58 0.37 0.92 0.56 CL [mL/h/kg] 100.70 81.67 71.00 32.90 146.30 113.40 V z [mL/kg] 1904.29 1090.85 1486.95 961.35 2711.57 1750.23 Accumulation index 1.01 0.02 1.00 1.00 1.01 0.01 Phase Ib, regimen 3: 4.0 mg/kg (n = 9) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 39 895.81 39 727.58 28 570.00 19 430.30 44 191.30 24 761.00 C max [ng/mL] 6201.54 2722.02 6060.00 3980.00 7730.00 3750.00 T max [h] 1.01 3.73 0.5 0.25 0.5 0.25 T ½ α [h] 1.80 2.11 1.05 0.56 2.01 1.45 CL [mL/h/kg] 120.24 72.06 100.70 62.75 183.53 120.78 V z [mL/kg] 2450.61 3498.82 1537.60 1129.48 2138.53 1009.05 Accumulation index 1.01 0.02 1 1 1.003 0.00 SD standard deviation, Q1 first quartile, Q3 third quartile, IQR interquartile range, AUC 0 − t area under the curve, C max maximum (peak) serum concentration, T max time to maximum (peak) serum concentration, T ½ α distribution serum half-time, CL serum clearance, Vz distribution volume, X not done/uknown The results suggested a two-compartment model. However, we observed large variability in the serum concentrations and PK parameter estimates among the patients in all included cohorts in both study phases. The serum concentration‒time profiles and derived non-compartmental estimated systemic CL and V z for all cohorts in both study phases did not reach the hepatic blood flow and largely exceeded the total body water in humans (1450 mL/min and 42 000 mL, respectively, in a human with body weight of 70 kg; approximately 1243 mL/h/kg and 600 mL/kg), suggesting a low extraction ratio and large distribution into tissues. Most of the PK profiles and serum levels indicated possible redistribution of MitoTam from the tissues back into the serum. During the release of MitoTam from tissue into the blood, its concentrations were often higher than at the time immediately after the end of intravenous administration. The redistribution of MitoTam together with the small numbers of patients in individual groups likely led to the relatively large SD for T max . The PK results of the individual cohorts in phases I and Ib are summarized below and in Table 2 . Phase I, doses 0.25–3.0 mg/kg After intravenous administration on D1, D3, and D5, the C max was reached at the mean time of 0.82 h (SD 2.24) and the mean T ½ α was 1.24 h (SD 1.16) combining data from all these cohorts. Serum MitoTam levels were generally measurable 36 h post-dose. The PK profiles of all subjects included in this phase declined in a multi-exponential manner. T ½ β ranged from 15.91 (SD 4.13) to 16.72 h (SD 7.73) for the 0.50–3.0 mg/kg cohorts and was 7.33 h (SD 4.69) for the 0.25 mg/kg cohort. The residual area was < 20% in all subjects included in this study phase. MRT and the total elimination time ranged from 7.19 to 15.73 h and 17.70 to 86.82 h, respectively, among the cohorts included in phase I. The mean estimated systemic CL of all phase I cohorts combined was 280.81 mL/h/kg (SD 214.41). The mean apparent V z was 7679 mL/kg (SD 6915). The PK profiles and serum levels suggest that MitoTam may be rereleased from the tissues back into the serum. The mean accumulation index for the included cohorts was 1.27 (SD 0.26). Phase I, doses 4.0‒6.0 mg/kg After a single intravenous dose, the C max was reached at the mean time of 0.88 h (SD 1.80). MitoTam was still measurable in serum at 168 h post-dose. The mean intensity and extent of exposure almost doubled between the 4.0 and 5.0 mg/kg cohorts, with C max of 3312 ng/mL (SD 824) vs. 6395 ng/mL (SD 3772), and AUC 0 − t of 27 421 ng*h/mL (SD 2488) vs. 47 833 ng*h/mL (SD 36 210). The 6.0 mg/kg cohort only included one subject, which prevented meaningful evaluation. The PK profiles of all subjects included in this study phase declined in a multi-exponential manner. T ½ β was 44.46 h (SD 4.49) and 46.28 h (SD 12.28) for the 4.0 and 5.0 mg/kg cohorts, and 27.41 h in the single subject in the 6.0 mg/kg cohort. The residual areas were < 20% in all subjects included in this study phase. MRT and the total elimination time ranged from 25.04 to 34.28 h and 202.06 to 225.16 h, respectively, across the cohorts included in phase I. The mean estimated CL for all patients included in these cohorts was 132.91 mL/h/kg (SD 61.50). The mean V z was 8852 mL/kg (SD 5645). The PK profiles and serum levels suggest that MitoTam may be rereleased from the tissue back into serum. Phase Ib, doses 1.0–4.0 mg/kg MitoTam was still measurable in serum at 24 h post-dose. There was no apparent relationship between the intensity or extent of exposure and increasing cycle number. The PK profiles of all subjects included in this study phase declined in a multi-exponential manner. The residual area was > 20% for most of the subjects included in this study phase; therefore, the extrapolated PK parameters were not reliable in these cases. The T ½ β, when estimable and reliable, ranged from 6.19 to 12.46 h for the 1.0 mg/kg dose, from 6.73 to 9.49 h for the 3.0 mg/kg dose, and from 6.17 to 11.62 h for the 4.0 mg/kg dose, considering all cycles. The MRT and time of total elimination, when estimable and reliable, ranged from 2.89 to 14.80 h and 30.82 to 56.91 h for the 1.0 mg/kg dose, from 7.43 to 10.74 h and 49.73 to 67.53 h for the 3.0 mg/kg dose, and from 7.66 to 12.21 h and 48.81 to 72.29 h for the 4.0 mg/kg dose, considering all cycles. T ½ α was significantly (p = 0.007) longer for the 4.0 mg/kg dose than the 3.0 mg/kg dose. The PK profiles and serum levels suggest that MitoTam may be rereleased from tissue back into serum. Because of the large intersubject variability in the serum MitoTam concentrations and PK parameter estimates across all cohorts in both study phases, we performed a longitudinal data analysis of T ½ β using GLMM in addition to the descriptive PK analysis for repeated observations across subjects. The PK analysis affirmed the significant effect of the dose on the AUC 0 − t and C max . The stochastic model formulations and the estimates of the statistically significant model parameters with corresponding p-values are given in Appendix A. Exposure–efficacy relationship We previously reported that the CBR was 37% (14/38) in the phase Ib part of the trial. 9 The CBR was 30% in regimen 1, 78% in regimen 2, and 11% in regimen 3. Because the unexpected difference in the CBR between the weekly regimens 2 and 3 is unlikely to be explained by a difference in dose (3.0 vs. 4.0 mg/kg), we divided the patients into subgroups according to the histogenetic origin of the tumor (Supplementary Table S9). A significant CBR (p = 0.018) was observed in tumors of mesodermal (ME) origin with RCC being the most frequent diagnosis in this subgroup. In patients with RCC (n = 6) treated in regimens 1 and 2, the CBR reached 83%. In this section, we summarize the relationship between PK parameters and the efficacy of MitoTam. The statistical analysis using GLM revealed non-significant effects of the PK parameters AUC 0 − t (borderline p = 0.072) and C max (p = 0.999) on the CBR (Appendix A). The PK parameters of responders and non-responders were also not significantly different (Table 3 ). In regimen 1, PK data from six responders and 14 non-responders were compared. In regimen 2, PK data from seven responders and two non-responders were evaluated. For regimen 3, there was one responder and eight non-responders. The mean AUC 0 − t was greater in responders than in non-responders in regimen 2 (42 373.73 ng*h/mL [SD 29 422.60] vs. 21 223.37 ng*h/mL [SD 11 552.67], respectively). The mean C max of responders was also greater than that of non-responders in regimen 2 (5908.97 ng/mL [SD 2980.33] vs. 3518.89 ng/mL [SD 672.14], respectively). The data in regimen 2 suggest a possible association between PK and CBR. Table 3 Pharmacokinetic parameters of responders and non-responders treated with MitoTam in phase Ib Regimen 1: responders (n = 6) Mean SD Median Q1 Q3 IQR AUC 0−t [ng*h/mL] 27 217.16 35 874.16 14 680.90 4247.60 30 964.50 26 716.90 C max [ng/mL] 3093.26 2644.58 2230.00 935.00 5370.00 4435.00 T ½ α [h] 0.82 1.14 0.39 0.31 0.67 0.36 Regimen 1: non-responders (n = 14) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 36 415.34 27 817.43 30 067.30 9955.20 57 898.60 47 943.40 C max [ng/mL] 4850.31 4017.83 3930.00 1827.50 7000.00 5172.50 T ½ α [h] 1.63 6.22 0.43 0.31 0.77 0.45 Regimen 2: responders (n = 7) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 42 373.73 29 422.60 37 605.80 17 328.70 57 150.00 39 821.30 C max [ng/mL] 5908.97 2980.33 5140.00 3410.00 7380.00 3970.00 T ½ α [h] 1.22 2.26 0.66 0.38 0.95 0.57 Regimen 2: non-responders (n = 2) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 21 223.37 11 552.67 15 790.50 2932.55 28 012.00 15 079.45 C max [ng/mL] 3518.89 672.14 2740.00 2085.00 5215.00 3130.00 T ½ α [h] 1.51 3.02 0.49 0.37 0.75 0.38 Regimen 3: responders (n = 1) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 56 051.02 88 631.26 17 248.55 14 352.45 78 629.75 64 277.30 C max [ng/mL] 7003.33 374.75 6020.00 2957.50 0952.50 7995.00 T ½ α [h] 1.28 0.79 1.47 0.39 2.07 1.68 Regimen 3: non-responders (n = 8) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 36 958.50 19 516.34 32 625.30 22 142.40 49 225.05 27 082.65 C max [ng/mL] 6055.76 2266.87 6060.00 4065.00 7580.00 3515.00 T ½ α [h] 1.87 2.24 1.04 0.56 2.08 1.51 SD standard deviation, Q1 first quartile, Q3 third quartile, IQR interquartile range, AUC 0 − t area under the curve, C max maximum (peak) serum concentration, T max time to maximum (peak) serum concentration, T ½ α distribution serum half-time, CL serum clearance To better explain the CBR in patients with RCC, we compared the PK parameters between responders with RCC (n = 5) and responders with other solid tumors (n = 8) (Table 4 ). Patients with RCC had a greater exposure to MitoTam, and the AUC 0 − t and C max were greater in regimens 1 and 2. However, we did not confirm the hypothesis that the PK parameters of patients with RCC differ to those of patients with other solid tumors. A significantly greater number of responders in regimen 2 (including 3 patients with RCC) than in regimen 3 excluding patients with RCC (78% vs. 11%, p = 0.001) supports the hypothesis that the CBR in regimen 2 is related to the diagnosis (i.e. RCC). Table 4 Pharmacokinetic parameters of responders with RCC and responders with other diagnoses treated with MitoTam in phase Ib Regimen 1: responders RCC (n = 2) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 38 307.03 50 468.62 13 503.85 5489.40 68 625.45 63 136.05 C max [ng/mL] 3213.88 3208.41 1570.00 941.50 6560.00 5618.50 T ½ α [h] 1.02 1.09 0.56 0.38 1.20 0.82 Regimen 1: responders non-RCC (n = 4) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 21 268.49 16 483.64 19 824.10 4274.68 32 202.38 27 927.70 C max [ng/mL] 3129.06 2341.53 3225.00 607.00 5195.00 4588.00 T ½ α [h] 0.66 1.08 0.34 0.24 0.58 0.34 Regimen 2: responders RCC (n = 3) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 41 820.56 20 982.20 49 690.00 21 111.25 57 802.55 36 691.30 C max [ng/mL] 6219.41 2671.45 5770.00 3955.00 8530.00 4575.00 T ½ α [h] 0.93 0.82 0.66 0.36 0.89 0.53 Regimen 2: responders non-RCC (n = 4) Mean SD Median Q1 Q3 IQR AUC 0 − t [ng*h/mL] 41 255.45 34 563.95 29 365.90 14 790.70 49 680.00 34 889.30 C max [ng/mL] 5338.64 3171.58 4480.00 2720.00 7302.50 4582.50 T ½ α [h] 1.44 2.87 0.57 0.41 1.08 0.67 SD standard deviation, Q1 first quartile, Q3 third quartile, IQR interquartile range, AUC 0 − t area under the curve, C max maximum (peak) serum concentration, T max time to maximum (peak) serum concentration, T ½ α distribution serum half-time The responders could repeat MitoTam therapy according to the trial protocol. Therefore, it was interesting to observe the exposure to MitoTam over time in these patients. In regimen 1, four patients repeated treatment; one patient received eight cycles (16 weeks), two received 12 cycles (24 weeks), and one received 16 cycles (32 weeks). Similarly, in regimen 2, one patient with a clinical benefit received 10 cycles (10 weeks) and two patients received 12 cycles (12 weeks) (Supplemental Table S9). MitoTam exposure did not change with increasing number of cycles, regardless of the treatment scheme (t.i.w. biweekly vs. q.w.) and regimen (dose 1.0 vs. 3.0 mg/kg). An increase in MitoTam accumulation was not observed these cases. Grade 3 (G3) systemic AEs were not observed in the subset of responders with prolonged MitoTam treatment. Thus, repeating treatment cycles can be considered safe with a low risk of AEs. Exposure–toxicity relationship In phase I, the incidence and grade of the most frequent toxicities (i.e. hematological AEs and fever) increased with increasing dose of MitoTam [ 9 ]. Pharmacologically, AUC 0 − t , C max , T ½ α and CL were significantly prolonged in the 4.0, 5.0, and 6.0 mg/kg cohorts (Table 2 ). The mean AUC 0 − t was disproportionally greater in the 5.0 mg/kg cohort compared with the 4.0 mg/kg cohort (47 833 ng*h/mL [SD 36 209] vs. 27 421 ng*h/mL [SD 2487], respectively). The same pattern was seen for both C max (6395 ng/mL [SD 3773] vs. 3312 ng/mL [SD 824], respectively) and CL (142.52 mL/h/kg vs. 49.7 mL/h/kg, respectively). Only one patient was enrolled in the 6.0 mg/kg cohort. In addition to G1‒G3 hematological AEs, this patient experienced a gastrointestinal toxicity (loss of appetite). The AUC 0 − t and C max were 119 682.50 ng*h/mL and 15 800 ng/mL, respectively, in this patient. Similarly, in phase Ib, hematological and gastrointestinal toxicities (nausea, vomiting, diarrhea, loss of appetite, weight loss) occurred in about 20% of patients in regimen 2 and in 70%‒80% of patients in regimen 3. T ½ α was significantly longer in regimen 3 than in regimen 2 (1.80 h [SD 2.11] vs. 1.28 h [SD 2.43], p = 0.007). The difference in T ½ α was not due to the variability in protein blood levels between individual patients, because the mean serum total protein concentrations were not significantly different between regimens 2 and 3 (73.08 g/L [SD 2.83] vs. 72.80 g/L [SD 6.98], respectively, p = 0.452). The mean serum albumin concentration in regimens 2 and 3 were 35.32 g/L (SD 3.15) and 35.30 g/L (SD 2.74), respectively (p = 0.723). Thus, our preliminary hypothesis of depleted albumin binding and a greater free fraction of MitoTam in regimen 3 was not confirmed. Table 5 shows the total serum protein and albumin levels for all cohorts in phase Ib. Because there were no significant differences in AUC 0 − t , C max , and CL, despite the different doses among these cohorts, we consider the 3.0 mg/kg dose to be optimal for further testing. Table 5 Serum total protein and albumin levels in all cohorts in phase Ib Regimen 1: 1.0 mg/kg (n = 20) Mean SD Median Q1 Q3 IQR Serum total protein (g/L) 71.00 9.23 72.65 66.85 75.95 9.1 Serum albumin (g/L) 34.20 3.07 33.70 32.78 37.15 4.38 Regimen 2: 3.0 mg/kg (n = 9) Mean SD Median Q1 Q3 IQR Serum total protein (g/L) 73.08 2.83 73.40 72.40 74.45 2.40 Serum albumin (g/L) 35.32 3.15 34.00 32.72 38.70 5.95 Regimen 3: 4.0 mg/kg (n = 9) Mean SD Median Q1 Q3 IQR Serum total protein (g/L) 72.80 6.98 71.50 66.35 79.05 12.70 Serum albumin (g/L) 35.30 2.74 34.70 33.45 36.95 3.50 SD standard deviation, Q1 first quartile, Q3 third quartile, IQR interquartile range Discussion Here, we performed detailed analyses of the PK profile of MitoTam and subanalyses of the clinically relevant endpoints of MitoTam phase I/Ib trial from the perspective of PK findings. To expand on the main PK results, we performed additional analyses to reflect the two treatment schemas and clinico-pathological variables, including the toxicity of MitoTam. Our approach was based on comparative statistical analysis of the calculated PK parameters, the role of the treatment regimen, the number of treatment cycles, the dose of MitoTam, sex, and baseline diagnosis. We paid special attention to whether the exceptional treatment outcomes in regimen 2 (CBR 78%) and in a virtual subcohort of patients with RCC (CBR 83%) were statistically significant or a random finding. All of these variables were tested to better understand their impact on the PK of MitoTam. The PK analysis showed a low extraction ratio and rapid distribution to the periphery. Most of the PK profiles indicated possible redistribution of MitoTam from the tissues or protein binding back into the serum, because secondary peaks in serum concentrations were occasionally observed. These secondary peaks were first observed in the 1.5 mg/kg cohort in phase I and subsequently observed in all cohorts in phase Ib. Preclinical biodistribution studies in animals [ 8 ] showed that MitoTam mostly accumulated in the kidneys, myocardium, lungs, and liver. Increased metabolism and high concentrations of the N -desmethyl MitoTam metabolite were observed in the liver and duodenum within 24 h post-dose, whereas the concentration in the kidneys increased steadily over a 1-week period, suggestive of accumulation rather than metabolization in this organ. The preclinical findings might help explain which tissues are the likely source of the secondary MitoTam peak. Overall, our clinical observations support the preclinical findings that MitoTam is excreted through the liver and bile ducts rather than via the kidneys. MitoTam was detectable as long as 168 h after the start of the infusion, supporting the idea of a large V z and high tissue affinity. We believe that the pig model used in preclinical studies [ 8 ] adequately addresses and explains the large volume of MitoTam distribution, however, clinically it is not feasible to confirm high tissue affinity since it is ethically unacceptable to take samples and evaluate PK parameters from patient tumors, liver and/or kidneys. Regarding the study’s primary objective—to determine the optimal and safe dose for further testing—we evaluated the relationship between the MitoTam dose and PK parameters. Elevated AUC 0 − t , C max , T ½ α and CL were recorded in the 4.0, 5.0, and 6.0 mg/kg cohorts in phase I and in regimen 3 of phase Ib. However, the differences in PK parameters between regimens 2 and 3 in phase Ib were generally not significant (AUC 0 − t , C max , and CL) with the exception of T ½ α. The prolonged serum half-life T ½ α was not related to the serum total protein and albumin concentrations. Our hypothesis that the elevated T ½ α at doses above 4.0 mg/kg may be related to depleted albumin binding and a subsequent greater free fraction of MitoTam proved to be wrong. Rather, it seems that the significantly longer T ½ α at doses above 4.0 mg/kg is related to the already exhausted terminal elimination process, which correlates with our clinical observations. We can conclude that the dose of 3.0 mg/kg (in regimen 2) is optimal for further testing from clinical and pharmacological perspectives. The AEs at the dose of 3.0 mg/kg were predominantly G1/2 anemia [ 9 ], a promising finding when compared to the safety profiles of other mitochondrial agents [ 2 – 6 ]. The risk of TE, which occurred in 13% of patients in phase Ib, may be related to the greater biodistribution of MitoTam in lung tissue, as observed in the preclinical model, and the lipophilic properties of the drug. Nevertheless, risk factors such as prior history of TE disease, the malignancy itself, and a long presence of an inadequate venous route (i.e. peripherally inserted central catheter) should be considered. Regarding the efficacy of MitoTam, preclinical studies demonstrated high anticancer activity in several mouse models of cancer [ 12 , 13 ]. Our hypothesis that the CBR would be related to the PK parameters, primarily the AUC 0 − t and C max , in regimens 2 and 3, was not confirmed. We think this is due to the high V z of MitoTam, the high permeability of MitoTam into cells, and its high binding to tissue components. We thus conclude that the high CBR of MitoTam in patients with RCC is due to preferential accumulation in the kidneys. The number of patients whose tumors originated in the mesodermal layer is too small to conclude whether MitoTam is effective in mesodermal-layer-derived tumors other than RCC. We searched for articles published in PubMed up to March 2023, and we found 88 studies in which cancers were targeted with mitochondrial inhibitors. Only 12 were active studies, almost exclusively in phases I or II. From this perspective, the successful antitumor effects of MitoTam observed in this trial hold great promise. The limitations of our study were discussed previously [ 9 ]. Some limitations, particularly the small number of participants, are inherent to phase I clinical trials. We are aware that the exposure-efficacy relationship is not well supported by data due to the small number of patients, resulting in confidence intervals for these comparisons being too wide and overlapping. The uneven representation of diagnoses between the study cohorts was due to the random recruitment of patients in the phase I trial, which was not powered to assess efficacy outcomes. The main technical limitation of our study was the use of two alternative treatment schemes in three regimens, which makes it difficult to compare the results among the patient groups. Therefore, we focused our PK analysis on the cohorts/regimens using a weekly dosing schedule. We believe that the results provide strong statistical evidence of clinical activity of MitoTam in tumors originating in the ME, which should be considered in future prospective phase II studies. Further confirmation of the clinical activity of MitoTam in patients with RCC is warranted. Conclusion We have demonstrated the safety and clinical activity of MitoTam from a pharmacological perspective. The PK parameters confirmed a two-compartment model with a large distribution of MitoTam into tissues and possible redistribution back to the serum. The detailed analysis focused on the relationship between the PK of MitoTam and its toxicity, and results support the previously recommended dose of 3.0 mg/kg with weekly administration for future studies. Patients with RCC showed greater exposure to MitoTam than other responders, which can be explained by its preferential accumulation in kidneys. Our data support further research of drug candidates targeting mitochondria. Declarations Acknowledgements We thank the patients who volunteered to participate in this study. The authors acknowledge Nicholas D. Smith for English language editing, which was funded by the Czech Health Foundation [NU21-03-00545]. #Dedicated to Dr. Josef Prchal who died unexpectedly while working on the manuscript and who was essential in the initiation and conduct of the clinical trial. Author contributions Zuzana Bielcikova: Conceptualization; Investigation; Methodology; Writing – original draft; Writing – review & editing. Olga Bartosova: Conceptualization; Formal analysis; Methodology; Writing – review & editing. Jan Stursa: Investigation; Methodology; Visualization; Writing – review & editing. Michal Pesta: Data curation; Formal analysis; Writing – review & editing. Jiri Neuzil: Funding Acquisition; Supervision; Writing – review & editing. Ondrej Slanar: Project Administration; Validation; Supervision; Writing – review & editing. Irena Stenglova Netikova: Methodology; Validation; Supervision; Writing – review & editing. Miroslava Bursova: Investigation; Validation; Writing – review & editing. Lukas Werner: Investigation; Methodology; Supervision; Writing – review & editing. Funding The MitoTam-01 trial was supported by SmartBrain s.r.o. (Czech Republic). The authors received no financial support for the research, authorship, and/or publication of this article. The work was supported in part by funding from the Czech Health Foundation [NU21-03-00545] and by Research Program 18—Strategy AV21 of the Czech Academy of Sciences and Programme EXCELES, No. LX22NPO5104, European Union – Next Generation EU. Competing interests Jiri Neuzil, Jan Stursa and Lukas Werner are owners of MitoTax s.r.o. that co-owns the MitoTam intellectual property. The remaining authors declare that they have no conflict of interest. Ethical approval The MitoTam-01 study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethical Review Committee of the General Faculty Hospital, Charles University. Consent to participate All patients signed written informed consent before undergoing any study-related procedure. Data availability The data that support the findings of this study are available on request from the corresponding author. References Sainero-Alcolado L, Liaño-Pons J, Ruiz-Pérez MV et al (2022) Targeting mitochondrial metabolism for precision medicine in cancer. Cell Death Differ 29:1304–1317. https://doi.org/10.1038/s41418-022-01022-y Ashkenazi A, Fairbrother WJ, Leverson JD et al (2017) From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov 16:273–284. https://doi.org/10.1038/nrd.2016.253 Yap TA, Daver N, Mahendra M et al (2023) Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials. Nat Med 29:115–126. https://doi.org/10.1038/s41591-022-02103-8 Alistar A, Morris BB, Desnoyer R, et al (2017) Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol 18:770–778. https://doi.org/10.1016/S1470-2045(17)30314-5 Christian S, Merz C, Evans L et al (2019) The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies. Leukemia 33:2403–2415. https://doi.org/10.1038/s41375-019-0461-5 Zhang X, Dang CV (2023) Time to hit pause on mitochondria-targeting cancer therapies. Nat Med 29:29–30. https://doi.org/10.1038/s41591-022-02129-y Rohlenova K, Schaphibulkij K, Stursa J et al (2017) Selective disruption of respiratory supercomplexes as a new strategy to suppress Her2 high breast cancer. Antiox Redox Signal 26:84–103. https://doi.org/10.1089/ars.2016.6677 Stemberkova-Hubackova S, Zobalova R, Dubisova M, et al (2022) Simultaneous targeting of mitochondrial metabolism and immune checkpoints as a new strategy for renal cancer therapy. Clin Transl Med 12:e645. https://doi.org/10.1002/ctm2.645 Bielcikova Z, Stursa J, Krizova L, et al (2023) Mitochondrially targeted tamoxifen in patients with metastatic solid tumours: an open-label, phase I/Ib single-centre trial. eClinMed 57:101873. https://doi.org/10.1016/j.eclinm.2023.101873 Kanji S, Hayes M, Ling A, et al (2015) Reporting guidelines for clinical pharmacokinetic studies: the ClinPK statement. Clin Pharmacokinet 54:783–795. https://doi.org/10.1007/s40262-015-0236-8 R Core Team (2021) R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna. https://www.R-project.org. Rohlenova K, Schaphibulkij K, Stursa J, et al (2017) Selective disruption of respiratory supercomplexes as a new strategy to suppress Her2 high breast cancer. Antiox Redox Signal 26:84–103. https://doi.org/10.1089/ars.2016.6677 Hubackova S, Rohlenova K, Davidova E, et al (2019) Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2. Cell Death Differ 26:276–290. https://doi.org/10.1038/s41418-018-0118-3 Additional Declarations Competing interest reported. Jiri Neuzil, Jan Stursa and Lukas Werner are owners of MitoTax s.r.o. that co-owns the MitoTam intellectual property. The remaining authors declare that they have no conflict of interest. Supplementary Files MitotamPKSupplement.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4669827","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":331374415,"identity":"ca0272d8-efe4-4ad1-8166-3fe47a2f0973","order_by":0,"name":"Olga Bartosova","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Olga","middleName":"","lastName":"Bartosova","suffix":""},{"id":331374417,"identity":"e2a6da28-f8dd-4e77-bc3e-2d94b6cf3632","order_by":1,"name":"Zuzana Bielcikova","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIie3QsWrDMBCA4TMGZbl0FhisV7DpWNO8ioTAXkIIdOnQIUbgbMmqvo2NwVn8AC5eEgKdOrgUSqFQKtN2Kah47KB/OgQfxwnA5frHcQL+BnhpxtkGhonE+yZYenoSgZHASCj/mzCdnV7Wd7C6mOX5cGwTsb9/itUarhc24mkuA93ADcFKUd6lQvfLWGmQvo34lJcBEhAFFQXwob6EPs3OCCWxEUKFescPQ9jpi7CHRihD0EaQShLMi3GLZ0hXh1HnVyOhNkLxkVzNd9TcIswtbRrGrTQkkpGNsG127vE1WbFtXT2/NQmGhypXeGv/sZ9lvx+sO1wul8s1pU/cnFKV9J7TAQAAAABJRU5ErkJggg==","orcid":"","institution":"General University Hospital in Prague","correspondingAuthor":true,"prefix":"","firstName":"Zuzana","middleName":"","lastName":"Bielcikova","suffix":""},{"id":331374419,"identity":"26cc4fa0-930f-4d4e-af41-b13d6d65b1a4","order_by":2,"name":"Jan Stursa","email":"","orcid":"","institution":"Institute of Clinical and Experimental Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Stursa","suffix":""},{"id":331374420,"identity":"6095521a-f479-4403-8b0b-d847f581e52b","order_by":3,"name":"Michal Pesta","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Michal","middleName":"","lastName":"Pesta","suffix":""},{"id":331374421,"identity":"3d367470-3de4-4a61-a5a2-d9127f2e5c30","order_by":4,"name":"Jiri Neuzil","email":"","orcid":"","institution":"Institute of Biotechnology of the Czech Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Jiri","middleName":"","lastName":"Neuzil","suffix":""},{"id":331374422,"identity":"13d3f6d8-dfaa-4958-9661-94e58f7f24c0","order_by":5,"name":"Miroslava Bursova","email":"","orcid":"","institution":"Charles University, General University Hospital in Prague","correspondingAuthor":false,"prefix":"","firstName":"Miroslava","middleName":"","lastName":"Bursova","suffix":""},{"id":331374423,"identity":"aa5bde1d-31e7-4212-b224-fec02255789c","order_by":6,"name":"Ondrej Slanar","email":"","orcid":"","institution":"General University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ondrej","middleName":"","lastName":"Slanar","suffix":""},{"id":331374424,"identity":"ebb5f1c0-8b1e-481b-93bd-446e959acbf9","order_by":7,"name":"Irena Stenglova Netikova","email":"","orcid":"","institution":"General University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Irena","middleName":"Stenglova","lastName":"Netikova","suffix":""},{"id":331374425,"identity":"699d2b3f-919a-4609-a9f6-956dd845bc62","order_by":8,"name":"Lukas Werner","email":"","orcid":"","institution":"Institute of Clinical and Experimental Medicine","correspondingAuthor":false,"prefix":"","firstName":"Lukas","middleName":"","lastName":"Werner","suffix":""}],"badges":[],"createdAt":"2024-07-01 18:26:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4669827/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4669827/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62112664,"identity":"f9c95308-d3b1-40f1-a550-f3d8579cacb2","added_by":"auto","created_at":"2024-08-09 12:14:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1431039,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4669827/v1/a13b9cfa-6673-40ac-953c-445d541611ba.pdf"},{"id":61090896,"identity":"3c6b3311-fadc-46ec-9523-2ab7cdb04812","added_by":"auto","created_at":"2024-07-25 13:05:58","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":236627,"visible":true,"origin":"","legend":"","description":"","filename":"MitotamPKSupplement.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4669827/v1/5bb95cd07a3d6a074fccc7bb.pdf"}],"financialInterests":"Competing interest reported. Jiri Neuzil, Jan Stursa and Lukas Werner are owners of MitoTax s.r.o. that co-owns the MitoTam intellectual property. The remaining authors declare that they have no conflict of interest.","formattedTitle":"Comprehensive statistical analysis of the pharmacokinetics, safety and clinical benefit rate of MitoTam in a single-center phase I/Ib trial in patients with metastatic solid tumors","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMany mitochondrial pathways, including oxidative phosphorylation (OXPHOS), fatty acid, glutamine, and one-carbon metabolism, are altered in tumors due to mutations in oncogenes, tumor suppressor genes, and metabolic enzymes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Mitocans are anticancer agents that act via targets on or within mitochondria. However, their translation from preclinical experiments has been challenging, and only a few compounds have entered early-stage clinical trials [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. To date, only one mitochondria-targeting agent (venetoclax) has been approved for chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Negative outcomes of several clinical trials [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] were critically assessed and generalized to the entire research concerning mitochondrial targeting [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Our research shows that targeting mitochondria is a plausible anticancer therapeutic strategy.\u003c/p\u003e \u003cp\u003eMitochondrially targeted tamoxifen (MitoTam) is a triphenylphosphonium (TPP\u003csup\u003e+\u003c/sup\u003e)-tagged mitocan that interferes with mitochondrial functions and complex I (CI)-dependent respiration [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. By \u0026lsquo;intercalating\u0026rsquo; into the inner mitochondrial membrane, MitoTam dissipates the mitochondrial membrane potential, promoting both apoptosis and necroptosis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The anticancer effect of MitoTam against renal cell carcinoma (RCC) was as efficient as immunotherapy with immune checkpoint inhibitors in an animal model [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe clinical efficacy and safety of MitoTam were evaluated in the phase I/Ib MitoTam-01 trial.\u003csup\u003e9\u003c/sup\u003e We reported a clinical benefit rate (CBR) of MitoTam of 37% (14/38) in patients with metastatic solid tumors, regardless of the diagnosis, and of 83% (5/6) among patients with RCC enrolled in the phase Ib part. All patients except one with CBR achieved disease stabilization following MitoTam treatment, as measured by RECIST 1.1 criteria. The maximum tolerated dose was 5.0 mg/kg, the penultimate dose in the series of nine doses tested. Systemic toxicities were mainly hematological adverse events (AEs) and fever. Local toxicities were related to the administration route, including risk of thromboembolic (TE) complications.\u003c/p\u003e \u003cp\u003eThe pharmacokinetic (PK) analysis was a primary endpoint of the MitoTam-01 trial to determine the total exposure, optimal dosing frequency, and potential accumulation of MitoTam. The initial routine PK analysis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], performed by an external evaluator, led us to more detailed and accurate assessment of results. In this article, we report a comprehensive and amended exploration of MitoTam PK, including the identification of parameters that may improve the odds of a clinical benefit or influence its toxicity. Herein, we also evaluated marginal PK parameters to obtain more insightful results. To obtain more robust data on the safety and efficacy of MitoTam, the original elimination half-life [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] was re-evaluated in this publication as distribution serum half-life (T\u0026frac12;α) and terminal serum elimination half-life (T\u0026frac12;β). We also report correlations between the CBR and PK parameters, including a critical assessment of their reliability, focusing on treatment regimens, number of treatment cycles, dose, sex, baseline diagnosis, and histogenetic origin of the disease.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eMitoTam-01 was an open-label, single-arm, non-randomized, single center phase I/Ib trial that evaluated the safety and efficacy of MitoTam. The study design was previously reported (EudraCT 2017-004441-25; registration date: November 1, 2017) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. All patients had previously undergone systemic anticancer therapy (three in median) that had been terminated. The ClinPK reporting checklist was consulted in the preparation of this report [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe phase I study evaluated the safety of a single cycle of MitoTam across nine escalating doses and two treatment schemas. Phase Ib evaluated the efficacy and safety of repeated doses of MitoTam in three different regimens. Supplemental Tables S1\u0026ndash;S7 present further information about the study design, including dosing and treatment schemes, administration of MitoTam, prohibited medications, and timing of blood sampling.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMitoTam analysis\u003c/h2\u003e \u003cp\u003eThe analysis of MitoTam and the internal standard (IS) MitoTam-D15 are described in detail in the Supplemental Methods.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDetermination of PK parameters\u003c/h2\u003e \u003cp\u003ePhoenix WinNonlin\u0026reg; software version 8.1 (Certara, USA) was used to calculate the PK parameters. Non-compartmental modeling used the linear trapezoidal/linear interpolation calculation methods. The best-fit method with uniform weighting was used to calculate the terminal elimination rate constant distribution and elimination half-life. Serum concentrations below the lower limit of quantification were set to zero. The following PK parameters were estimated for each subject, sampling day, and cycle: maximum serum concentration (C\u003csub\u003emax\u003c/sub\u003e), area under the serum concentration curve (AUC\u003csub\u003e0‒\u003cem\u003et\u003c/em\u003e\u003c/sub\u003e), time to reach the maximum serum concentration (T\u003csub\u003emax\u003c/sub\u003e), distribution serum half-life (T\u003csub\u003e\u0026frac12;\u003c/sub\u003eα), terminal serum elimination half-life (T\u003csub\u003e\u0026frac12;\u003c/sub\u003eβ), mean residence time (MRT), serum clearance (CL), volume of distribution (V\u003csub\u003ez\u003c/sub\u003e), and accumulation index. Analysis of PK variance was used to test the effects of phase, cohort, cycle, day, and sex at a 5% significance level for AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e and C\u003csub\u003emax\u003c/sub\u003e. PK parameters requiring extrapolation of the elimination phase to infinity (T\u003csub\u003e\u0026frac12;\u003c/sub\u003eα, T\u003csub\u003e\u0026frac12;\u003c/sub\u003eβ, MRT, and CL) were not considered as the main parameters in statistical correlation analysis. These extrapolated PK parameters should be evaluated cautiously.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics, including the empirical mean, standard deviation (SD), empirical median, minimum, first quartile (i.e., 25th percentile), empirical median, third quartile (i.e., 75th percentile), and maximum, were calculated for the key variables. These parameters are also presented as matrices in pairwise plots. Where appropriate we used random effects mixed models (generalized linear mixed models [GLMM]) in addition to the descriptive PK analysis.\u003c/p\u003e \u003cp\u003eThe theoretical test level was set to 0.05. Results with p values of \u0026lt;\u0026thinsp;0.05 were considered statistically significant and reported as such in this manuscript. R statistical software by R Core Team (2021) version 4.1.1 (released on August 10, 2021) was used [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. All of the stochastic model formulations together with the estimates of the statistically significant model parameters and corresponding p-values are given in Appendix A.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eSeventy-five patients were enrolled between May 23, 2018, and July 22, 2020, comprising 37 in phase I and 38 in phase Ib. Their characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Supplemental Tables S8 and S9. We found no significant differences in the baseline characteristics among treatment groups that could be relevant to the exposure, distribution, metabolism, or clearance of MitoTam that might influence its PK.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic data of enrolled patients (N\u0026thinsp;=\u0026thinsp;75)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDose of MitoTam, mg/kg (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge, years, mean (SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSex (M/F)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHeight, cm, mean (SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eWeight, kg, mean (SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e, mean (SD)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhase I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.25 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e59.75 (9.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e172.75 (9.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e72.67 (16.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e24.61 (2.59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.5 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50.67 (8.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e167.00 (7.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e69.83 (19.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e24.85 (5.87)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.0 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47.33 (3.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e166.67 (13.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e83.67 (4.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e30.55 (3.96)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.5 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e59.67 (5.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e172.00 (10.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e106.33 (13.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e36.66 (8.35)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.25 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e62.17 (8.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e167.00 (8.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e78.20 (13.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e28.03 (3.93)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.0 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61.40 (6.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e169.80 (11.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e83.60 (17.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e29.22 (6.74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.0 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e65.33 (8.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e165.33 (5.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e66.33 (6.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e24.46 (3.78)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.0 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e66.50 (3.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e172.67 (8.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e83.83 (17.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e27.79 (3.72)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.0 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e68.00 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e180.00 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e87.00 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e26.85 (0.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhase Ib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.0 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e59.05 (9.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12/8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e172.35 (9.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e77.16 (18.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e26.25 (5.10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.0 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63.78 (8.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e167.67 (8.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e79.11 (17.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e28.06 (5.77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.0 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63.56 (5.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6/3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e176.22 (8.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e83.89 (13.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e27.01 (3.95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eSD\u003c/em\u003e standard deviation, \u003cem\u003eM\u003c/em\u003e males, \u003cem\u003eF\u003c/em\u003e females, \u003cem\u003eBMI\u003c/em\u003e body mass index\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePharmacokinetics\u003c/h2\u003e \u003cp\u003eSerial PK data were analyzed for three-times-weekly (t.i.w.; n\u0026thinsp;=\u0026thinsp;27) and once-weekly (q.w.; n\u0026thinsp;=\u0026thinsp;10) dosing schemes in phase I, and in phase Ib (n\u0026thinsp;=\u0026thinsp;20 vs. n\u0026thinsp;=\u0026thinsp;18). Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows The PK parameters for the nine cohorts in phase I (0.25‒6.0 mg/kg) and three in phase Ib (1.0, 3.0, and 4.0 mg/kg).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePharmacokinetic parameters of MitoTam for all cohorts and regimens in phases I and Ib\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003ePhase I, cohort 0.25 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e960.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e740.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e499.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e280.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1720.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1440.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e [ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e302.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e223.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e304.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e133.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e385.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e251.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL [mL/h/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e412.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e314.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e299.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e136.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e725.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e588.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e [mL/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7315.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7843.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3527.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2919.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11 661.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8742.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccumulation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003ePhase I, cohort 0.5 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4447.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7805.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1495.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e979.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2148.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1169.80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e [ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1037.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1523.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e500.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e229.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e764.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e535.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL [mL/h/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e265.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e167.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e271.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e127.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e404.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e276.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e [mL/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 023.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8281.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 019.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6713.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13 545.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6832.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccumulation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003ePhase I, cohort 1.0 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3068.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1535.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2160.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1925.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4405.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2480.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e [ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1019.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e772.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e669.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e469.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1565.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1095.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL [mL/h/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e342.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e123.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e403.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e186.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e447.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e261.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e [mL/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9588.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5745.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8293.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4887.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14 132.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9244.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccumulation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003ePhase I, cohort 1.5 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 595.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 224.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3925.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3115.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15 371.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12 255.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e [ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2486.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2424.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1530.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e723.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4180.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3457.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL [mL/h/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e379.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e221.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e356.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e177.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e591.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e413.80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e [mL/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9975.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6374.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 149.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3601.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16 261.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12 660.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccumulation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003ePhase I, cohort 2.25 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 553.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 461.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8242.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37 726.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e29 484.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e [ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2734.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1509.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2435.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1547.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3450.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1902.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL [mL/h/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e171.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e160.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e111.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e316.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e264.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e [mL/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5347.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6527.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2174.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1357.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8769.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7411.80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccumulation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003ePhase I, cohort 3.0 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 783.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 643.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 704.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 005.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e39 495.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e27 490.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e [ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4204.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3739.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3040.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1867.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5035.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3167.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL [mL/h/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e177.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e109.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e225.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e279.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e229.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e [mL/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4384.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2887.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5406.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1000.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7257.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6257.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccumulation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003ePhase I, cohort 4.0 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 421.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2487.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 932.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23 914.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29 417.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5503.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e [ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3311.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e824.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2980.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2510.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4445.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1935.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL [mL/h/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e141.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e132.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e131.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e160.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e29.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e [mL/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9135.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1612.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8434.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7606.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11 364.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3757.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccumulation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003ePhase I, cohort 5.0 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC \u003csub\u003e0\u0026minus;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 833.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 209.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 341.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 513.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e66 428.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e44 915.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e [ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6395.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3772.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6100.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2670.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10 067.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7397.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL [mL/h/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e142.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e133.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e87.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e216.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e129.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e [mL/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9858.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6127.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7716.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4221.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17 917.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e13 696.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccumulation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003ePhase I, cohort 6.0 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119 682.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e119 682.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e59 841.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e59 841.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e [ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 800\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 800\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7900\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7900\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL [mL/h/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e [mL/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1964.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1964.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e982.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e982.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccumulation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003ePhase Ib, regimen 1: 1.0 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 891.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 941.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 427.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9929.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e49 214.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e39 284.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e [ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4461.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3497.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3670.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2116.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4183.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL [mL/h/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e62.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e49.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e [mL/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2325.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2467.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1319.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e892.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2813.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1920.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccumulation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003ePhase Ib, regimen 2: 3.0 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 181.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 141.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 585.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 334.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e53 474.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e38 139.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e [ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5483.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2991.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4800.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2860.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7302.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4442.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL [mL/h/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e71.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e146.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e113.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e [mL/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1904.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1090.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1486.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e961.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2711.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1750.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccumulation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003ePhase Ib, regimen 3: 4.0 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 895.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 727.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 570.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19 430.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e44 191.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24 761.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e [ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6201.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2722.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6060.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3980.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7730.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3750.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL [mL/h/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e120.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e183.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e120.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e [mL/kg]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2450.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3498.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1537.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1129.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2138.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1009.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccumulation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eSD\u003c/em\u003e standard deviation, \u003cem\u003eQ1\u003c/em\u003e first quartile, \u003cem\u003eQ3\u003c/em\u003e third quartile, \u003cem\u003eIQR\u003c/em\u003e interquartile range, \u003cem\u003eAUC\u003c/em\u003e\u003csub\u003e\u003cem\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/em\u003e\u003c/sub\u003e area under the curve, \u003cem\u003eC\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e maximum (peak) serum concentration, \u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e time to maximum (peak) serum concentration, \u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u0026frac12;\u003c/em\u003e\u003c/sub\u003e\u003cem\u003eα\u003c/em\u003e distribution serum half-time, \u003cem\u003eCL\u003c/em\u003e serum clearance, \u003cem\u003eVz\u003c/em\u003e distribution volume, \u003cem\u003eX\u003c/em\u003e not done/uknown\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe results suggested a two-compartment model. However, we observed large variability in the serum concentrations and PK parameter estimates among the patients in all included cohorts in both study phases. The serum concentration‒time profiles and derived non-compartmental estimated systemic CL and V\u003csub\u003ez\u003c/sub\u003e for all cohorts in both study phases did not reach the hepatic blood flow and largely exceeded the total body water in humans (1450 mL/min and 42 000 mL, respectively, in a human with body weight of 70 kg; approximately 1243 mL/h/kg and 600 mL/kg), suggesting a low extraction ratio and large distribution into tissues. Most of the PK profiles and serum levels indicated possible redistribution of MitoTam from the tissues back into the serum. During the release of MitoTam from tissue into the blood, its concentrations were often higher than at the time immediately after the end of intravenous administration. The redistribution of MitoTam together with the small numbers of patients in individual groups likely led to the relatively large SD for T\u003csub\u003emax\u003c/sub\u003e. The PK results of the individual cohorts in phases I and Ib are summarized below and in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003ePhase I, doses 0.25\u0026ndash;3.0 mg/kg\u003c/h2\u003e \u003cp\u003eAfter intravenous administration on D1, D3, and D5, the C\u003csub\u003emax\u003c/sub\u003e was reached at the mean time of 0.82 h (SD 2.24) and the mean T\u003csub\u003e\u0026frac12;\u003c/sub\u003eα was 1.24 h (SD 1.16) combining data from all these cohorts. Serum MitoTam levels were generally measurable 36 h post-dose. The PK profiles of all subjects included in this phase declined in a multi-exponential manner. T\u003csub\u003e\u0026frac12;\u003c/sub\u003eβ ranged from 15.91 (SD 4.13) to 16.72 h (SD 7.73) for the 0.50\u0026ndash;3.0 mg/kg cohorts and was 7.33 h (SD 4.69) for the 0.25 mg/kg cohort. The residual area was \u0026lt;\u0026thinsp;20% in all subjects included in this study phase. MRT and the total elimination time ranged from 7.19 to 15.73 h and 17.70 to 86.82 h, respectively, among the cohorts included in phase I. The mean estimated systemic CL of all phase I cohorts combined was 280.81 mL/h/kg (SD 214.41). The mean apparent V\u003csub\u003ez\u003c/sub\u003e was 7679 mL/kg (SD 6915). The PK profiles and serum levels suggest that MitoTam may be rereleased from the tissues back into the serum. The mean accumulation index for the included cohorts was 1.27 (SD 0.26).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePhase I, doses 4.0‒6.0 mg/kg\u003c/h2\u003e \u003cp\u003eAfter a single intravenous dose, the C\u003csub\u003emax\u003c/sub\u003e was reached at the mean time of 0.88 h (SD 1.80). MitoTam was still measurable in serum at 168 h post-dose. The mean intensity and extent of exposure almost doubled between the 4.0 and 5.0 mg/kg cohorts, with C\u003csub\u003emax\u003c/sub\u003e of 3312 ng/mL (SD 824) vs. 6395 ng/mL (SD 3772), and AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e of 27 421 ng*h/mL (SD 2488) vs. 47 833 ng*h/mL (SD 36 210). The 6.0 mg/kg cohort only included one subject, which prevented meaningful evaluation. The PK profiles of all subjects included in this study phase declined in a multi-exponential manner. T\u003csub\u003e\u0026frac12;\u003c/sub\u003eβ was 44.46 h (SD 4.49) and 46.28 h (SD 12.28) for the 4.0 and 5.0 mg/kg cohorts, and 27.41 h in the single subject in the 6.0 mg/kg cohort. The residual areas were \u0026lt;\u0026thinsp;20% in all subjects included in this study phase. MRT and the total elimination time ranged from 25.04 to 34.28 h and 202.06 to 225.16 h, respectively, across the cohorts included in phase I. The mean estimated CL for all patients included in these cohorts was 132.91 mL/h/kg (SD 61.50). The mean V\u003csub\u003ez\u003c/sub\u003e was 8852 mL/kg (SD 5645). The PK profiles and serum levels suggest that MitoTam may be rereleased from the tissue back into serum.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePhase Ib, doses 1.0\u0026ndash;4.0 mg/kg\u003c/h2\u003e \u003cp\u003eMitoTam was still measurable in serum at 24 h post-dose. There was no apparent relationship between the intensity or extent of exposure and increasing cycle number. The PK profiles of all subjects included in this study phase declined in a multi-exponential manner. The residual area was \u0026gt;\u0026thinsp;20% for most of the subjects included in this study phase; therefore, the extrapolated PK parameters were not reliable in these cases. The T\u003csub\u003e\u0026frac12;\u003c/sub\u003eβ, when estimable and reliable, ranged from 6.19 to 12.46 h for the 1.0 mg/kg dose, from 6.73 to 9.49 h for the 3.0 mg/kg dose, and from 6.17 to 11.62 h for the 4.0 mg/kg dose, considering all cycles. The MRT and time of total elimination, when estimable and reliable, ranged from 2.89 to 14.80 h and 30.82 to 56.91 h for the 1.0 mg/kg dose, from 7.43 to 10.74 h and 49.73 to 67.53 h for the 3.0 mg/kg dose, and from 7.66 to 12.21 h and 48.81 to 72.29 h for the 4.0 mg/kg dose, considering all cycles. T\u003csub\u003e\u0026frac12;\u003c/sub\u003eα was significantly (p\u0026thinsp;=\u0026thinsp;0.007) longer for the 4.0 mg/kg dose than the 3.0 mg/kg dose. The PK profiles and serum levels suggest that MitoTam may be rereleased from tissue back into serum.\u003c/p\u003e \u003cp\u003eBecause of the large intersubject variability in the serum MitoTam concentrations and PK parameter estimates across all cohorts in both study phases, we performed a longitudinal data analysis of T\u003csub\u003e\u0026frac12;\u003c/sub\u003eβ using GLMM in addition to the descriptive PK analysis for repeated observations across subjects. The PK analysis affirmed the significant effect of the dose on the AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e and C\u003csub\u003emax\u003c/sub\u003e. The stochastic model formulations and the estimates of the statistically significant model parameters with corresponding p-values are given in Appendix A.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eExposure\u0026ndash;efficacy relationship\u003c/h2\u003e \u003cp\u003eWe previously reported that the CBR was 37% (14/38) in the phase Ib part of the trial.\u003csup\u003e9\u003c/sup\u003e The CBR was 30% in regimen 1, 78% in regimen 2, and 11% in regimen 3. Because the unexpected difference in the CBR between the weekly regimens 2 and 3 is unlikely to be explained by a difference in dose (3.0 vs. 4.0 mg/kg), we divided the patients into subgroups according to the histogenetic origin of the tumor (Supplementary Table S9). A significant CBR (p\u0026thinsp;=\u0026thinsp;0.018) was observed in tumors of mesodermal (ME) origin with RCC being the most frequent diagnosis in this subgroup. In patients with RCC (n\u0026thinsp;=\u0026thinsp;6) treated in regimens 1 and 2, the CBR reached 83%. In this section, we summarize the relationship between PK parameters and the efficacy of MitoTam.\u003c/p\u003e \u003cp\u003eThe statistical analysis using GLM revealed non-significant effects of the PK parameters AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e (borderline p\u0026thinsp;=\u0026thinsp;0.072) and C\u003csub\u003emax\u003c/sub\u003e (p\u0026thinsp;=\u0026thinsp;0.999) on the CBR (Appendix A). The PK parameters of responders and non-responders were also not significantly different (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In regimen 1, PK data from six responders and 14 non-responders were compared. In regimen 2, PK data from seven responders and two non-responders were evaluated. For regimen 3, there was one responder and eight non-responders. The mean AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e was greater in responders than in non-responders in regimen 2 (42 373.73 ng*h/mL [SD 29 422.60] vs. 21 223.37 ng*h/mL [SD 11 552.67], respectively). The mean C\u003csub\u003emax\u003c/sub\u003e of responders was also greater than that of non-responders in regimen 2 (5908.97 ng/mL [SD 2980.33] vs. 3518.89 ng/mL [SD 672.14], respectively). The data in regimen 2 suggest a possible association between PK and CBR.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePharmacokinetic parameters of responders and non-responders treated with MitoTam in phase Ib\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 1: responders\u0026nbsp; (n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC \u003csub\u003e0\u0026minus;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 217.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 874.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 680.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4247.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30 964.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26 716.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;[ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3093.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2644.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2230.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e935.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5370.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4435.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 1: non-responders (n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 415.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 817.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 067.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9955.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57 898.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e47 943.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;[ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4850.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4017.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3930.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1827.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7000.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5172.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 2:\u0026nbsp;responders\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 373.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 422.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37 605.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17 328.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57 150.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e39 821.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;[ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5908.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2980.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5140.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3410.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7380.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3970.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 2:\u0026nbsp;non-responders (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 223.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 552.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 790.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2932.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28 012.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15 079.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;[ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3518.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e672.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2740.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2085.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5215.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3130.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 3: responders (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 051.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88 631.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 248.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 352.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e78 629.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e64 277.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;[ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7003.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e374.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6020.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2957.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0952.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7995.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 3: non-responders (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 958.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 516.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 625.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22 142.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e49 225.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e27 082.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;[ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6055.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2266.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6060.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4065.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7580.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3515.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eSD\u003c/em\u003e standard deviation, \u003cem\u003eQ1\u003c/em\u003e first quartile, \u003cem\u003eQ3\u003c/em\u003e third quartile, \u003cem\u003eIQR\u003c/em\u003e interquartile range, \u003cem\u003eAUC\u003c/em\u003e\u003csub\u003e\u003cem\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/em\u003e\u003c/sub\u003e area under the curve, \u003cem\u003eC\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e maximum (peak) serum concentration, \u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e time to maximum (peak) serum concentration, \u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u0026frac12;\u003c/em\u003e\u003c/sub\u003e\u003cem\u003eα\u003c/em\u003e distribution serum half-time, \u003cem\u003eCL\u003c/em\u003e serum clearance\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTo better explain the CBR in patients with RCC, we compared the PK parameters between responders with RCC (n\u0026thinsp;=\u0026thinsp;5) and responders with other solid tumors (n\u0026thinsp;=\u0026thinsp;8) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Patients with RCC had a greater exposure to MitoTam, and the AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e and C\u003csub\u003emax\u003c/sub\u003e were greater in regimens 1 and 2. However, we did not confirm the hypothesis that the PK parameters of patients with RCC differ to those of patients with other solid tumors. A significantly greater number of responders in regimen 2 (including 3 patients with RCC) than in regimen 3 excluding patients with RCC (78% vs. 11%, p\u0026thinsp;=\u0026thinsp;0.001) supports the hypothesis that the CBR in regimen 2 is related to the diagnosis (i.e. RCC).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePharmacokinetic parameters of responders with RCC and responders with other diagnoses treated with MitoTam in phase Ib\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 1: responders RCC (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 307.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 468.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 503.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5489.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e68 625.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e63 136.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;[ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3213.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3208.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1570.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e941.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6560.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5618.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 1: responders non-RCC (n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 268.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 483.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 824.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4274.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32 202.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e27 927.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;[ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3129.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2341.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3225.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e607.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5195.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4588.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 2: responders RCC (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 820.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 982.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 690.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 111.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57 802.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e36 691.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;[ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6219.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2671.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5770.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3955.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8530.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4575.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 2: responders non-RCC (n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e [ng*h/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 255.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 563.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 365.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 790.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e49 680.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e34 889.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;[ng/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5338.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3171.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4480.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2720.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7302.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4582.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e\u0026frac12;\u003c/sub\u003eα [h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eSD\u003c/em\u003e standard deviation, \u003cem\u003eQ1\u003c/em\u003e first quartile, \u003cem\u003eQ3\u003c/em\u003e third quartile, \u003cem\u003eIQR\u003c/em\u003e interquartile range, \u003cem\u003eAUC\u003c/em\u003e\u003csub\u003e\u003cem\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/em\u003e\u003c/sub\u003e area under the curve, \u003cem\u003eC\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e maximum (peak) serum concentration, \u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e time to maximum (peak) serum concentration, \u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u0026frac12;\u003c/em\u003e\u003c/sub\u003e\u003cem\u003eα\u003c/em\u003e distribution serum half-time\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe responders could repeat MitoTam therapy according to the trial protocol. Therefore, it was interesting to observe the exposure to MitoTam over time in these patients. In regimen 1, four patients repeated treatment; one patient received eight cycles (16 weeks), two received 12 cycles (24 weeks), and one received 16 cycles (32 weeks). Similarly, in regimen 2, one patient with a clinical benefit received 10 cycles (10 weeks) and two patients received 12 cycles (12 weeks) (Supplemental Table S9). MitoTam exposure did not change with increasing number of cycles, regardless of the treatment scheme (t.i.w. biweekly vs. q.w.) and regimen (dose 1.0 vs. 3.0 mg/kg). An increase in MitoTam accumulation was not observed these cases. Grade 3 (G3) systemic AEs were not observed in the subset of responders with prolonged MitoTam treatment. Thus, repeating treatment cycles can be considered safe with a low risk of AEs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eExposure\u0026ndash;toxicity relationship\u003c/h2\u003e \u003cp\u003eIn phase I, the incidence and grade of the most frequent toxicities (i.e. hematological AEs and fever) increased with increasing dose of MitoTam [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Pharmacologically, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, C\u003csub\u003emax\u003c/sub\u003e, T\u003csub\u003e\u0026frac12;\u003c/sub\u003eα and CL were significantly prolonged in the 4.0, 5.0, and 6.0 mg/kg cohorts (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The mean AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e was disproportionally greater in the 5.0 mg/kg cohort compared with the 4.0 mg/kg cohort (47 833 ng*h/mL [SD 36 209] vs. 27 421 ng*h/mL [SD 2487], respectively). The same pattern was seen for both C\u003csub\u003emax\u003c/sub\u003e (6395 ng/mL [SD 3773] vs. 3312 ng/mL [SD 824], respectively) and CL (142.52 mL/h/kg vs. 49.7 mL/h/kg, respectively). Only one patient was enrolled in the 6.0 mg/kg cohort. In addition to G1‒G3 hematological AEs, this patient experienced a gastrointestinal toxicity (loss of appetite). The AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e and C\u003csub\u003emax\u003c/sub\u003e were 119 682.50 ng*h/mL and 15 800 ng/mL, respectively, in this patient.\u003c/p\u003e \u003cp\u003eSimilarly, in phase Ib, hematological and gastrointestinal toxicities (nausea, vomiting, diarrhea, loss of appetite, weight loss) occurred in about 20% of patients in regimen 2 and in 70%‒80% of patients in regimen 3. T\u003csub\u003e\u0026frac12;\u003c/sub\u003eα was significantly longer in regimen 3 than in regimen 2 (1.80 h [SD 2.11] vs. 1.28 h [SD 2.43], p\u0026thinsp;=\u0026thinsp;0.007). The difference in T\u003csub\u003e\u0026frac12;\u003c/sub\u003eα was not due to the variability in protein blood levels between individual patients, because the mean serum total protein concentrations were not significantly different between regimens 2 and 3 (73.08 g/L [SD 2.83] vs. 72.80 g/L [SD 6.98], respectively, p\u0026thinsp;=\u0026thinsp;0.452). The mean serum albumin concentration in regimens 2 and 3 were 35.32 g/L (SD 3.15) and 35.30 g/L (SD 2.74), respectively (p\u0026thinsp;=\u0026thinsp;0.723). Thus, our preliminary hypothesis of depleted albumin binding and a greater free fraction of MitoTam in regimen 3 was not confirmed. Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e shows the total serum protein and albumin levels for all cohorts in phase Ib. Because there were no significant differences in AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, C\u003csub\u003emax\u003c/sub\u003e, and CL, despite the different doses among these cohorts, we consider the 3.0 mg/kg dose to be optimal for further testing.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSerum total protein and albumin levels in all cohorts in phase Ib\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 1: 1.0 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum total protein (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e66.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e75.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum albumin (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 2: 3.0 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum total protein (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e72.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e74.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum albumin (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eRegimen 3: 4.0 mg/kg\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIQR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum total protein (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e71.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e66.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e79.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum albumin (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eSD\u003c/em\u003e standard deviation, \u003cem\u003eQ1\u003c/em\u003e first quartile, \u003cem\u003eQ3\u003c/em\u003e third quartile, \u003cem\u003eIQR\u003c/em\u003e interquartile range\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eHere, we performed detailed analyses of the PK profile of MitoTam and subanalyses of the clinically relevant endpoints of MitoTam phase I/Ib trial from the perspective of PK findings. To expand on the main PK results, we performed additional analyses to reflect the two treatment schemas and clinico-pathological variables, including the toxicity of MitoTam. Our approach was based on comparative statistical analysis of the calculated PK parameters, the role of the treatment regimen, the number of treatment cycles, the dose of MitoTam, sex, and baseline diagnosis. We paid special attention to whether the exceptional treatment outcomes in regimen 2 (CBR 78%) and in a virtual subcohort of patients with RCC (CBR 83%) were statistically significant or a random finding. All of these variables were tested to better understand their impact on the PK of MitoTam.\u003c/p\u003e \u003cp\u003eThe PK analysis showed a low extraction ratio and rapid distribution to the periphery. Most of the PK profiles indicated possible redistribution of MitoTam from the tissues or protein binding back into the serum, because secondary peaks in serum concentrations were occasionally observed. These secondary peaks were first observed in the 1.5 mg/kg cohort in phase I and subsequently observed in all cohorts in phase Ib. Preclinical biodistribution studies in animals [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] showed that MitoTam mostly accumulated in the kidneys, myocardium, lungs, and liver. Increased metabolism and high concentrations of the \u003cem\u003eN\u003c/em\u003e-desmethyl MitoTam metabolite were observed in the liver and duodenum within 24 h post-dose, whereas the concentration in the kidneys increased steadily over a 1-week period, suggestive of accumulation rather than metabolization in this organ. The preclinical findings might help explain which tissues are the likely source of the secondary MitoTam peak. Overall, our clinical observations support the preclinical findings that MitoTam is excreted through the liver and bile ducts rather than via the kidneys.\u003c/p\u003e \u003cp\u003eMitoTam was detectable as long as 168 h after the start of the infusion, supporting the idea of a large V\u003csub\u003ez\u003c/sub\u003e and high tissue affinity. We believe that the pig model used in preclinical studies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] adequately addresses and explains the large volume of MitoTam distribution, however, clinically it is not feasible to confirm high tissue affinity since it is ethically unacceptable to take samples and evaluate PK parameters from patient tumors, liver and/or kidneys.\u003c/p\u003e \u003cp\u003eRegarding the study\u0026rsquo;s primary objective\u0026mdash;to determine the optimal and safe dose for further testing\u0026mdash;we evaluated the relationship between the MitoTam dose and PK parameters. Elevated AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, C\u003csub\u003emax\u003c/sub\u003e, T\u003csub\u003e\u0026frac12;\u003c/sub\u003eα and CL were recorded in the 4.0, 5.0, and 6.0 mg/kg cohorts in phase I and in regimen 3 of phase Ib. However, the differences in PK parameters between regimens 2 and 3 in phase Ib were generally not significant (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, C\u003csub\u003emax\u003c/sub\u003e, and CL) with the exception of T\u003csub\u003e\u0026frac12;\u003c/sub\u003eα. The prolonged serum half-life T\u003csub\u003e\u0026frac12;\u003c/sub\u003eα was not related to the serum total protein and albumin concentrations. Our hypothesis that the elevated T\u003csub\u003e\u0026frac12;\u003c/sub\u003eα at doses above 4.0 mg/kg may be related to depleted albumin binding and a subsequent greater free fraction of MitoTam proved to be wrong. Rather, it seems that the significantly longer T\u003csub\u003e\u0026frac12;\u003c/sub\u003eα at doses above 4.0 mg/kg is related to the already exhausted terminal elimination process, which correlates with our clinical observations. We can conclude that the dose of 3.0 mg/kg (in regimen 2) is optimal for further testing from clinical and pharmacological perspectives.\u003c/p\u003e \u003cp\u003eThe AEs at the dose of 3.0 mg/kg were predominantly G1/2 anemia [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], a promising finding when compared to the safety profiles of other mitochondrial agents [\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The risk of TE, which occurred in 13% of patients in phase Ib, may be related to the greater biodistribution of MitoTam in lung tissue, as observed in the preclinical model, and the lipophilic properties of the drug. Nevertheless, risk factors such as prior history of TE disease, the malignancy itself, and a long presence of an inadequate venous route (i.e. peripherally inserted central catheter) should be considered.\u003c/p\u003e \u003cp\u003eRegarding the efficacy of MitoTam, preclinical studies demonstrated high anticancer activity in several mouse models of cancer [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Our hypothesis that the CBR would be related to the PK parameters, primarily the AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e and C\u003csub\u003emax\u003c/sub\u003e, in regimens 2 and 3, was not confirmed. We think this is due to the high V\u003csub\u003ez\u003c/sub\u003e of MitoTam, the high permeability of MitoTam into cells, and its high binding to tissue components. We thus conclude that the high CBR of MitoTam in patients with RCC is due to preferential accumulation in the kidneys. The number of patients whose tumors originated in the mesodermal layer is too small to conclude whether MitoTam is effective in mesodermal-layer-derived tumors other than RCC.\u003c/p\u003e \u003cp\u003eWe searched for articles published in PubMed up to March 2023, and we found 88 studies in which cancers were targeted with mitochondrial inhibitors. Only 12 were active studies, almost exclusively in phases I or II. From this perspective, the successful antitumor effects of MitoTam observed in this trial hold great promise.\u003c/p\u003e \u003cp\u003eThe limitations of our study were discussed previously [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Some limitations, particularly the small number of participants, are inherent to phase I clinical trials. We are aware that the exposure-efficacy relationship is not well supported by data due to the small number of patients, resulting in confidence intervals for these comparisons being too wide and overlapping. The uneven representation of diagnoses between the study cohorts was due to the random recruitment of patients in the phase I trial, which was not powered to assess efficacy outcomes. The main technical limitation of our study was the use of two alternative treatment schemes in three regimens, which makes it difficult to compare the results among the patient groups. Therefore, we focused our PK analysis on the cohorts/regimens using a weekly dosing schedule. We believe that the results provide strong statistical evidence of clinical activity of MitoTam in tumors originating in the ME, which should be considered in future prospective phase II studies. Further confirmation of the clinical activity of MitoTam in patients with RCC is warranted.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe have demonstrated the safety and clinical activity of MitoTam from a pharmacological perspective. The PK parameters confirmed a two-compartment model with a large distribution of MitoTam into tissues and possible redistribution back to the serum. The detailed analysis focused on the relationship between the PK of MitoTam and its toxicity, and results support the previously recommended dose of 3.0 mg/kg with weekly administration for future studies. Patients with RCC showed greater exposure to MitoTam than other responders, which can be explained by its preferential accumulation in kidneys. Our data support further research of drug candidates targeting mitochondria.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the patients who volunteered to participate in this study.\u0026nbsp;The authors acknowledge Nicholas D. Smith for English language editing, which was funded by\u0026nbsp;the Czech Health Foundation [NU21-03-00545].\u003c/p\u003e\n\u003cp\u003e#Dedicated to Dr. Josef Prchal who died unexpectedly while working on the manuscript and who was essential in the initiation and conduct of the clinical trial.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eZuzana Bielcikova:\u003c/strong\u003e Conceptualization; Investigation; Methodology; Writing \u0026ndash; original draft; Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOlga Bartosova:\u003c/strong\u003e Conceptualization; Formal analysis; Methodology; Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJan Stursa:\u003c/strong\u003e Investigation; Methodology; Visualization; Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMichal Pesta:\u003c/strong\u003e Data curation; Formal analysis; Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJiri Neuzil:\u003c/strong\u003e Funding Acquisition; Supervision; Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOndrej Slanar:\u003c/strong\u003e Project Administration; Validation; Supervision; Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIrena Stenglova Netikova:\u003c/strong\u003e Methodology; Validation; Supervision; Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMiroslava Bursova:\u003c/strong\u003e Investigation; Validation; Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLukas Werner:\u003c/strong\u003e Investigation; Methodology; Supervision; Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe MitoTam-01 trial was supported by SmartBrain s.r.o. (Czech Republic).\u0026nbsp;The authors received no financial support for the research, authorship, and/or publication of this article.\u0026nbsp;The work was supported in part by funding from the Czech Health Foundation [NU21-03-00545] and\u0026nbsp;by Research Program 18\u0026mdash;Strategy AV21 of the Czech Academy of Sciences and Programme EXCELES, No. LX22NPO5104, European Union \u0026ndash; Next Generation EU.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJiri Neuzil, Jan Stursa and Lukas Werner are owners of MitoTax s.r.o. that co-owns the MitoTam intellectual property. The\u0026nbsp;remaining authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe MitoTam-01 study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethical Review Committee of the General Faculty Hospital, Charles University.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients signed written informed consent before undergoing any study-related procedure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSainero-Alcolado L, Lia\u0026ntilde;o-Pons J, Ruiz-P\u0026eacute;rez MV et al (2022) Targeting mitochondrial metabolism for precision medicine in cancer. Cell Death Differ 29:1304\u0026ndash;1317. https://doi.org/10.1038/s41418-022-01022-y\u003c/li\u003e\n\u003cli\u003eAshkenazi A, Fairbrother WJ, Leverson JD et al (2017) From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov 16:273\u0026ndash;284. https://doi.org/10.1038/nrd.2016.253\u003c/li\u003e\n\u003cli\u003eYap TA, Daver N, Mahendra M et al (2023) Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials. Nat Med 29:115\u0026ndash;126. https://doi.org/10.1038/s41591-022-02103-8\u003c/li\u003e\n\u003cli\u003eAlistar A, Morris BB, Desnoyer R, et al (2017) Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol 18:770\u0026ndash;778. https://doi.org/10.1016/S1470-2045(17)30314-5\u003c/li\u003e\n\u003cli\u003eChristian S, Merz C, Evans L et al (2019) The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies. Leukemia 33:2403\u0026ndash;2415. https://doi.org/10.1038/s41375-019-0461-5\u003c/li\u003e\n\u003cli\u003eZhang X, Dang CV (2023) Time to hit pause on mitochondria-targeting cancer therapies. Nat Med 29:29\u0026ndash;30. https://doi.org/10.1038/s41591-022-02129-y\u003c/li\u003e\n\u003cli\u003eRohlenova K, Schaphibulkij K, Stursa J et al (2017) Selective disruption of respiratory supercomplexes as a new strategy to suppress Her2\u003csup\u003ehigh\u003c/sup\u003e breast cancer. Antiox Redox Signal 26:84\u0026ndash;103. https://doi.org/10.1089/ars.2016.6677\u003c/li\u003e\n\u003cli\u003eStemberkova-Hubackova S, Zobalova R, Dubisova M, et al (2022) Simultaneous targeting of mitochondrial metabolism and immune checkpoints as a new strategy for renal cancer therapy. Clin Transl Med 12:e645. https://doi.org/10.1002/ctm2.645\u003c/li\u003e\n\u003cli\u003eBielcikova Z, Stursa J, Krizova L, et al (2023) Mitochondrially targeted tamoxifen in patients with metastatic solid tumours: an open-label, phase I/Ib single-centre trial. eClinMed 57:101873. https://doi.org/10.1016/j.eclinm.2023.101873\u003c/li\u003e\n\u003cli\u003eKanji S, Hayes M, Ling A, et al (2015) Reporting guidelines for clinical pharmacokinetic studies: the ClinPK statement. Clin Pharmacokinet 54:783\u0026ndash;795. https://doi.org/10.1007/s40262-015-0236-8\u003c/li\u003e\n\u003cli\u003eR Core Team (2021) R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna. https://www.R-project.org.\u003c/li\u003e\n\u003cli\u003eRohlenova K, Schaphibulkij K, Stursa J, et al (2017) Selective disruption of respiratory supercomplexes as a new strategy to suppress Her2\u003csup\u003ehigh\u003c/sup\u003e breast cancer. Antiox Redox Signal 26:84\u0026ndash;103. https://doi.org/10.1089/ars.2016.6677\u003c/li\u003e\n\u003cli\u003eHubackova S, Rohlenova K, Davidova E, et al (2019) Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2. Cell Death Differ 26:276\u0026ndash;290. https://doi.org/10.1038/s41418-018-0118-3\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"MitoTam, pharmacokinetics, phase I/Ib, clinical benefit rate, safety, renal cell carcinoma","lastPublishedDoi":"10.21203/rs.3.rs-4669827/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4669827/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMitoTam, the first mitochondrial inhibitor to disrupt complex I (CI)-dependent respiration, previously showed antitumor activity against renal cell carcinoma (RCC) with a good safety profile. We investigated the relationships of pharmacokinetic (PK) parameters, biodistribution, and patient baseline diagnosis with the clinical outcome and toxicity of MitoTam.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn the phase I/Ib MitoTam-01 trial, patients with metastatic solid tumors were treated with MitoTam monotherapy. PK parameters were calculated separately for the doses used in both trial phases. Data were analyzed descriptive analyses and using the generalized linear model framework as stochastic test.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe non-compartmental analysis of PK parameters showed that the extent of exposure was positively correlated with the dose. Most of the PK profiles suggested that MitoTam was redistributed from the tissues or from protein binding back into the blood circulation, with very low accumulation. The exposure‒efficacy relationship did not show significant differences between responders and non-responders in phase Ib. However, the AUC\u003csub\u003e0-t\u003c/sub\u003e and C\u003csub\u003emax\u003c/sub\u003e values were greater in RCC patients than in responders with other diagnoses. These data are consistent with the preclinical findings showing preferential MitoTam accumulation in kidneys and the high clinical benefit rate in RCC patients in the phase Ib part.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThese comprehensive analyses demonstrate the impact of MitoTam on the clinical benefit rate that is related to the dose and corresponding PK parameters, as well the underlying diagnosis. The PK data supported the previously recommended dose of 3.0 mg/kg weekly for future trials.\u003c/p\u003e\u003ch2\u003eRegistration:\u003c/h2\u003e \u003cp\u003eEudraCT 2017-004441-25 (November 1, 2017)\u003c/p\u003e","manuscriptTitle":"Comprehensive statistical analysis of the pharmacokinetics, safety and clinical benefit rate of MitoTam in a single-center phase I/Ib trial in patients with metastatic solid tumors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-25 13:05:53","doi":"10.21203/rs.3.rs-4669827/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0b307aad-256b-4cb4-b4a5-1868a0260829","owner":[],"postedDate":"July 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-09T12:06:42+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-25 13:05:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4669827","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4669827","identity":"rs-4669827","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}