Precision dosing of intravenous busulfan in infants patients undergoing bone marrow transplantation in China

Precision dosing of intravenous busulfan in infants patients undergoing bone marrow transplantation in China | 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 Article Precision dosing of intravenous busulfan in infants patients undergoing bone marrow transplantation in China Duan-fang Shao, Shun-qiao Feng, Zhao-xia Zhang, Tao Hu, Meng-ze Hu, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5251996/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 Veno-occlusive disease (VOD) is a severe adverse reaction to busulfan-containing regimens used in the preparation of children for hematopoietic stem cell transplantation (HSCT). We previously found that the youngest children have a greater risk of VOD, and a high busulfan C max is more likely to occur after the first two doses. We conducted a retrospective pharmacokinetic analysis of IV (intravenous) busulfan in infants undergoing a hematopoietic stem cell transplantation (HSCT) and described its relation to transplantation outcomes. Thirty-four infants (median age, 8.5 months) underwent HSCT at The Hospital of Capital Institute of Pediatrics from October 2018 through April 2024 and received IV busulfan every 6 hour (h) as part of their conditioning regimen. Initial busulfan doses were based on actual patient weight: <9 kg, 0.75–1.1 mg/kg per dose (mean dose 0.91 mg/kg, mean 13.45 doses, mean total dosage 12.35 mg/kg ); 9–12 kg, 0.82–1.2 mg/kg per dose (mean dose 0.96 mg/kg, mean 13 doses, mean total dosage 12.84 mg/kg). Plasma busulfan concentrations were obtained after the first or fifth dose. The fourth or the eighth and subsequent busulfan (Bu/BSF) doses were adjusted to achieve an area under the concentration versus time curve (AUC) of 1125 µmol*min/L ± 10% depending on donor source and disease. After the first dose, median AUC was 758.2 (530.02-1335.9) µmol*min/L. Thirteen infants had Bu IV dose decreased by > 10%. Neutrophil and platelet recoveries, grade 2–4 aGVHD, and nonrelapse mortality (NRM) incidences were 97%, 94%, 11.7%, and 2.9%, respectively. Relapse incidence was 5.9%. Incidence of veno-occlusive disease, hemorrhagic cystitis, and lung toxicities were 9%, 3%, and 6%, respectively. OS and EFS were 91% and 91%. Health sciences/Diseases Health sciences/Medical research Figures Figure 1 Figure 2 Introduction Children may differ from adults with regards to drug pharmacokinetics, both in response to treatment (efficacy) and their susceptibility to side effects (safety). Variability in pharmacokinetics is one factor which alters drug exposure, and this in turn might explain differences in the (un)wanted responses (pharmacodynamics) between children. Characterization of variability in pharmacokinetics between neonates, infants, children and adolescents is therefore important, especially for drugs with a small therapeutic window such as busulfan (BSF). Commonly used as part of the conditioning regimen prior to hematopoietic stem cells transplantation (HSCT), BSF-based treatments represent a preferred alternative to total body irradiation (TBI), especially in pediatric patients 1 . Typically, BSF is administered over 4 days in the form of 2-hour (h) infusions every 6h. The US FDA labeling recommends that the initial dose is based on body weight. The recommended dose is 1.1 mg/kg for patients ≤ 12 kg and 0.8 mg/kg for patients ≥ 12 kg with an acceptable BU AUC being 900 to 1350 ± 5% µmolar × minute 2 (C SS = 650 ng/mL to 924 ng/mL). The EMA algorithm is more complicated because it has 5 dose cohorts (Table 1 ) that are based on actual body weight to achieve a BU AUC of 900 µmolar × minute to 1500 µmolar × minute (C SS = 650 ng/mL to 1026 ng/mL). Table 1 Busulfan manufacturer dosing guidelines Patient weight(kg) IV busulfan dose(mg/kg/dose) <9 1 9 to<16 1.2 16 to<23 1.1 23 to34 0.8 These 2 different dosing recommendations were based on popPK modeling 3 . A greater proportion of patients achieve the target exposure when using EMA dosing (70%) than when using the FDA dosing (57%), based on simulations using a popPK model built using data from 1610 HCT recipients (92% of whom were children) 4 . Thus, the EMA dosing is recommended. Intravenous (IV) busulfan shows large pharmacokinetic (PK) variability between children and the optimal exposure range in children has not been precisely defined 3 . Significant busulfan intra-individual variability may occur in children who receive a HSCT and is hardly predictable. Indeed, patients undergoing BSF therapy typically experience a significant decrease in drug clearance (CLBSF) shortly after treatment initiation 5 , which complicates the execution of TDM. Performing TDM repeatedly over therapy appears to be the best way to accurately estimate busulfan exposure and perform precision dosing 5 , 6 . However, the optimal dose, optimal AUC target, and dosing schedule of i.v. busulfan in children remain undecided. We conducted a retrospective analysis of a cohort of infant patients who underwent HSCT and had a wide range of exposure to busulfan. The aim was to establish the optimal busulfan exposure in relation to efficacy and toxicity. Materials and methods Patients: Thirty-four infants with a median age of 8.5 months (range, 5 to 12 months) were included in the pharmacokinetic study, which was approved by the institutional review board of the Hospital of Capital Institute of Pediatrics. Informed consent was obtained from parents of all patients. All patients had indwelling central venous catheters from which blood samples were obtained. Clinical data for the thirty-four infants are listed in Table 2 . Table 2 Patient Characteristics Patient No. Age/sex (m) Weight (kg) Disease Treatment GVHD prophylaxis Donor type Total doses Total Dosage of Busulfan(mg/kg) 1 8/M 6.8 MAL CLAG + Bu + Mel ATG + MTX + CNI + MMF MMRD 12.00 12.00 2 5/M 7.5 SCID Bu + FLU + CTX CNI + MP MMCB 10.00 8.53 3 11.5/M 9 PKD Bu + FLU + CTX PTcy + CNI + MMF MUD 14.00 13.77 4 8/M 8 AML IDA + Ara-c + Bu + FLu + CTX CNI + MMF MMCB 16.00 16.00 5 8/M 10.5 FD Bu + FLU ATG + PTcy + CNI + MMF MMRD 15.00 13.70 6 5/M 5.8 WAS Bu + FLU ATG + PTcy + CNI + MMF MMRD 16.00 16.40 7 10/M 8.6 AEL CL + Ara + IDA + Bu + Cy CNI + MMF MMCB 16.00 17.40 8 12/M 6.5 AML CLAG + Bu + Cy CNI + MMF MMCB 12.00 10.10 9 11/F 9.5 WAS FLu + Bu + TT ATG + CNI + MMF MMCB 12.00 12.10 10 8/M 7.8 WAS Bu + FLu + CTX ATG + PTcy + CNI + MMF MMRD 16.00 12.30 11 11.5/M 8 AML Bu + FLu + CTX CNI + MMF MMCB 10.00 8.18 12 6.5/M 6 PID Bu + FLu + CTX ATG + CNI + MMF MCB 12.00 10.60 13 8.5/F 9 PKD FLu + Bu + TT ATG + PTcy + CNI + MMF MMRD 14.00 14.33 14 5.5/M 8.65 AML Ara-c + Bu + FLu + CTX CNI + MMF MMCB 12.00 8.47 15 12/M 11 MPS IIIa Bu + FLu + CTX ATG + CNI + MMF MMCB 16.00 17.70 16 11/F 10 WAS Bu + FLu + CTX + TT ATG + CNI + MMF MMCB 12.00 12.90 17 12/M 6 PID Bu + FLu + CTX + TT ATG + CNI + MMF MMCB 12.00 12.00 18 12/F 8.2 WAS Bu + FLu + CTX ATG + CNI + MMF MMCB 12.00 12.68 19 6.5/M 9 WAS Bu + FLu ATG + PTcy + CNI + MMF MMRD 16.00 16.60 20 4.5/M 6.5 WAS FLu + Bu + TT PTcy + CNI + MMF MSD 16.00 12.92 21 8/M 8.3 FHL FLu + Bu + TT + VP16 PTcy + CNI + MMF MRD 16.00 12.53 22 8.5/M 8 JMML Ara + FLu + Bu ATG + CNI + MMF MMCB 16.00 16.00 23 8.5/F 8.3 HIGM Flu + Bu + TT ATG + PTcy + CNI + MMF MUD 12.00 11.20 24 9/M 10.1 WAS Flu + Bu + TT ATG + CNI + MMF MCB 11.00 10.50 25 6.8/M 6 WAS Bu + FLu + CTX + TT CNI + MMF MMCB 16.00 12.33 26 9/M 9.8 AML Bu + FLu + CTX CNI + MMF MMCB 11.00 8.33 27 7.8/F 8.95 CGD Flu + Bu + TT ATG + PTcy + CNI + MMF MMRD 12.00 8.95 28 11/M 8.5 CGD Bu + FLu + CTX ATG + PTcy + CNI + MMF MMRD 16.00 17.76 29 10.8/M 8.8 CGD Bu + FLu + CTX + TT ATG + CNI + MMF MMCB 14.00 16.52 30 11.4/M 8.2 ALL Ara + FLu + Bu CNI + MMF MMCB 12.00 10.56 31 9.5/F 12 JMML FLu + Bu + Mel ATG + PTcy + CNI + MMF MUD 12.00 9.75 32 11/M 9 WAS Flu + Bu + TT ATG + CNI + MMF MMCB 12.00 11.64 33 5.6/M 8 JMML Ara + FLu + Bu PTcy + CNI + MMF MSD 12.00 12 34 10.5/F 8.2 AML-M7 CLAG + Bu + Cy ATG + CsA + MTX MMRD 12 12.96 Abbreviations: MAL, acute mixed leukemia; SCID, X-linked severe immunodeficiency; PKD, Pyruvate kinase deficiency; AML, acute myeloid leukemia; FD, Farber disease ; WAS, Wiskott-Aldrich syndrome; AEL, Acute erythroid leukemia; PID, primary immune deficiency ; MPS, Mucopolysaccharidosis; FHL, familialhemophagocytic syndrome; JMML, Juvenile myelomonocytic leukaemia; HIGM, IgM increased immune deficiency; CGD, chronic granulomatous disease; ALL, Acute Lymphocytic Leukemia; Bu, busulfan; CPM, cyclophosphamide; L-PAM, melphalan; TTP, thiotepa, MMUD/MMRD, mismatched unrelated/related donor; MSD, matched sibling donor; MUD, matched unrelated donor; MMCB, mismatched cord blood Busulfan Concentration Data: Busulfan was administered over 3 or 4 consecutive days as a 2-h infusion administered every 6h in most patients. The initial dose ranged from 0.75 to 1.2 mg/kg, depending on the patient’s body weight and disease, in accordance with the European summary of product characteristics and our past experience 7 , 8 . Bu was preferentially utilized for workday admissions as PK’s were not available for two consecutive days (weekend PK’s were not routinely available during this time period). Because, the high intra-individual variability and possible time-dependent changes in clearance (Cl) during elimination, TDM of busulfan and dose individualization were performed for all patients in order to achieve the target IV BU exposure (AUC) is the first-dose AUC with an acceptable range of 720 to 950 ± 5% µmolar × minute and the fifth-dose AUC 1125 ± 5% µmolar × minute after every 6 hour (Q6H) dosing. This target Bu AUC was chosen based on original studies by Grochow and colleagues as well as our historical experience 5 , 9 – 12 . The blood samples were obtained prior to infusion and at 60, 120, 150, 180, 240 and 360 min (trough level) post-infusion. The next Bu dose was not administered until the 360 min blood sample had been obtained. Blood samples were drawn from the catheter lumen that was not used for dose administration. TDM could be subsequently performed again with the same sampling scheme during the last 2 or 3 days of therapy in some patients, in order to control the observed AUC and adjust the dose again if necessary. The decision to repeat TDM was taken at the physician’s discretion. When the first-dose and fifth-dose AUC was within the target range, no repeat PK analysis was performed. If a patient’s first-dose or fifth-dose AUC was outside the target range, the dosage was adjusted on the 5th or 9th dose and repeat PK analysis was performed as needed to achieve the target AUC. When adjustments were made they were typically a 15–35% decrease or up to a 20% increase from the prior dosage. Total Bu exposure, described by an estimated total cumulative AUC, was retrospectively calculated as previously published by Bartelink and colleagues 13 . Endpoints and definitions: The main study endpoints were event-free survival (EFS) and overall survival (OS) after HSCT, with a follow up of at least 4 months. EFS was defined as alive with engraftment (> 95% chimerism) and without evident relapse in those children who underwent transplantation for malignant disease. EFS was calculated from the time of transplant until death, relapse or graft failure, whichever occurred first. OS was the time between transplantation and death of any causes. Primary graft failure was defined as failure to achieve a sustained absolute neutrophil count of ≥ 500/µL in the absence of persistent or relapsed disease. Regarding acute toxicity was evaluated according to the Bearman score 14 . VOD was assessed using both the Baltimore and McDonald criteria 15 . aGVHD was diagnosed and graded according to the criteria of Glucksberg et al 16 . Chimerism > 95% was considered full donor chimerism; donor chimerism > 10% and < 95% was considered mixed chimerism; graft rejection was defined as donor chimerism < 10%. Statistical analysis: Overall survival (OS) and DFS probabilities were estimated using the Kaplan-Meier method. The Mann-Whitney U test was used for continuous variables, while the chi-squared test was used for categorical variables. The logistic regression model was used to relate Bu AUC, donor source, GVHD prophylaxis and other patient characteristics (weight, age, and disease) to probability of engraftment or toxicity. Significant difference was set at a level of p < 0.05. SPSS 19.0 (Mathsoft, Seattle, WA, USA) was used for data analyses. Results Table 2 summarizes patient, disease, and transplantation characteristics of 34 infants, 23 (67.6%) were below 9kg and 26 (76.5%) were male. Median age was 8.5 (5–12) months, average ± SD weight was 8.35 ± 1.48 kg, and average ± SD dose received was 0.93 ± 0.11 mg/kg; <9 kg, 0.75–1.1 mg/kg initial per dose (mean dose 0.91mg/kg, mean 13.45 doses, mean total dosage 12.35mg/kg ); 9–12 kg, 0.82–1.2 mg/kg initial per dose (mean dose 0.96mg/kg, mean 13 doses, mean total dose 12.84mg/kg). We also obtained samples at steady state for 33 infants. Among these 33 infants, no dose adjustments were made for seven infants, the dose was increased for six patients, and the dose was decreased for 20 patients. Twelve (35%) infants had a malignant disease and nineteen (58%) were immunodeficiency related diseases. Eleven infants received a graft from a related donor and 5 from an unrelated donor; 18 infants received a CBT. Twenty-nine (85%) patients received IV Bu + FIu as conditioning. All patients received CNI as GVHD prophylaxis associated with MMF (94%) or PTcy (35%). The median number of CD34 + cells infused was 8.5 *10 6 /kg for bone marrow + peripheral blood/peripheral blood stem cell and 4.3 *10 5 /kg for CBT. Busulfan Dose and Pharmacokinetics: Pharmacokinetic parameters after the first, fifth and ninth doses in 21, 31 and 16 infants are given in Table 3 . There were wide inter-individual variations in terms of busulfan disposition with maximal concentration ranging from 794.1 to 2229.0 ng/ml at steady state of the fifth dose. The mean systemic exposure(AUC) is 819.91 ± 185.56 µmol*min/L after the first dose、1261.32 ± 349.772µmol*min/L after the fifth dose and 1235.2 ± 342.69 after the ninth dose. The study population exhibit a wide range in total AUC, from 11646.1 to 27339.9 µmol*min/L, we were unable to prove a correlation between total busulfan exposure and underlying disease (Fig. 1 ). Large inter-individual and intra-individual variations in the pharmacokinetics of busulfan were evident, necessitating varying dose adjustments at day + 2 to + 4 of busulfan treatment. Figure 2 displays the individual changes in busulfan CL in those 20 infants. For all parameters, both increase and decrease occurs. The average magnitude of the changes was limited, but large variability was observed. A majority of patients experienced a decrease in busulfan CL. Regarding CL, the mean value was signifcantly decreased on D2 compared with D1 (p < 0.001), with a mean change of − 26.9%. The majority of patients (n = 19 [95%]) experienced a decrease in CL(DC) between D1 and D2, with a mean decrease of − 28.5% (range − 40.1 to − 9.7%), including 3, and 16 infants with a decrease between 9.7% and 20%, and ≥ 20%, respectively. One infant (5%) experienced an increase in CL, with a change of + 3.9%. Various TDM strategies and effect on exposure are shown in Table 4 . In infants who underwent TDM on D1, D2, and D3, the proportion of overexposure was the lowest (0/9). Performing TDM only on D2 appears insufficient to minimize overexposure, the rate of which would have been 28.5% (2/7). By contrast, performing TDM on D1 and D2 appears more effective in reducing inter-patient variability in AUC cum and prevent overexposure, as the rate would have been similar to the 3-day TDM strategy (0/11). Table 3 Pharmacokinetic Parameters After the First、Fifth、Ninth and Thirteenth Doses of Busulfan First Dosing Fifth Dosing Ninth Dosing Thirteenth Dosing Patient No. C max (ng/mL) C min (ng/mL) AUC 0 − 6h (umol*min/L) First dosage (mg/kg) C max (ng/mL) C min (ng/mL) AUC 0 − 6h (umol*min/L) Fifth dosage (mg/kg) C max (ng/mL) C min (ng/mL) AUC 0 − 6h (umol*min/L) Ninth dosage (mg/kg) Thirteenth dosage (mg/kg) 1 ND ND ND 1.00 NA NA 1091.5 1 ND ND ND 1 2 ND ND ND 1.00 1821 953 1993.2 1 1047 468 1084.7 0.53 3 ND ND ND 1.10 1405 824 1621.2 1.1 ND ND ND 0.89 0.89 4 ND ND ND 1.00 982 233 914.6 1 ND ND ND 1 1 5 ND ND ND 1.14 2038 1211 2207.8 1.14 1406 925 1565.9 0.76 0.76 6 ND ND ND 1.10 1513 482 1284.4 1.1 ND ND ND 1.1 0.83 7 983 306 878.13 1.00 ND ND ND 1.1 ND ND ND 1.1 1.1 8 ND ND ND 1.00 1698 646 1614.6 1 892 501 1004.3 0.69 9 ND ND ND 1.05 1348 508 1316.7 1.05 1235 565 1207.6 0.947 10 627 280 651.8 0.80 1000 308 892.2 0.8 ND ND ND 0.8 0.8 11 1285 415 1015.5 0.94 1536 531 1498.99 0.94 913 505 955.79 0.5 12 887 346 713.1 0.83 1480 573 1416.02 1 ND ND ND 0.83 13 779 236 625.48 0.90 878 258 830.94 0.9 931 322 926.9 1.11 1.11 14 773 554 837.93 0.82 1130 745 1344.7 0.82 ND ND ND 0.59 0.59 15 1161 391 962.6 1.20 1013 561 1014.92 1.1 ND ND ND 1.1 16 650 291 654.08 1.00 1034 507 1111.94 1.1 ND ND ND 1.1 17 705 439 725.87 1.00 991 605 1127.95 1 ND ND ND 1 18 874 265 723.51 0.98 1095 457 1019.915 1.09 ND ND ND 1.09 19 1023 382 1002.31 1.11 1284 548 964.07 1.11 1446 502 1315.71 1.11 0.88 20 487 362 530.02 0.77 945 616 1062.24 0.92 1132 478 1175.09 0.77 0.77 21 965 268 747.69 0.78 887 341 961.084 0.78 905 352 911.328 0.78 0.78 22 905 294 790.7 1.00 1344 384 1135.32 1 ND ND ND 1 1 23 1294 416 918.6 0.96 1606 575 1384.4 0.93 ND ND ND 0.9 24 ND ND ND 1.10 1682 829 1755.5 1.1 1238 697 1370.8 0.6 25 790 304 702.19 0.75 1294 392 969.24 0.75 ND ND ND 0.75 0.83 26 747 452 813.82 0.82 1254 611 1249.513 0.816 2899 958 2279.7226 0.714 27 ND ND ND 1.00 2229 886 1952 1 1120 563 1237.33 0.67 28 901 215 731 1.06 1109 423 1098.66 1.18 1446 364 1300.67 1.18 29* ND ND ND 1.00 659 265 672.22 1.0 815 192 727.53 1.25 1.42 30 778 344 758.22 0.75 794.1 300 839.79 0.75 1125 426 1189.77 1 31 1244 671 1335.9 1.16 1275 655 1421.4 0.83 921 424 1002.4 0.583 32 1117 838 1099.7 1.20 1048 436 1174.3 0.9 ND ND ND 0.9 33 ND ND ND 1.00 NA NA 1026.9 1 ND ND ND 1 34 ND ND ND 1.08 1136 473 1066.3 1.08 ND ND ND 1.08 Min 487 215 530.02 0.75 794.1 233 830.94 0.75 892 322 911.33 0.5 0.59 Max 1294 838 1335.90 1.2 2229.00 1211.00 2207.8 1.18 2899 958 2279.72 1.18 1.1 mean 903.57 384.23 819.91 0.98 1294.97 562.36 1261.32 0.98 1267.35 538.92 1235.20 0.88 0.85 SD 222.55 149.78 185.56 0.13 352.14 218.65 349.772 0.12 508.49 196.31 342.69 0.19 0.14 ND Not determined, NA Not available, *Combined with rifampicin Table 4 Various therapeutic drug monitoring strategies and predicted exposure in 32 infants who underwent therapeutic drug monitoring on different days. Parameter TDM on D1, D2 and D3 (actual strategy)(n = 9) TDM on D2 (n = 7) TDM on D1 and D2 (n = 11) TDM on D2 and D3 (n = 5) Mean AUC cum ±SD(umol*min/L) 15028.93 ± 2482.92 15423.18 ± 3149.84 14172.52 ± 1791.06 19363.01 ± 4783.29 Median AUC cum (minimum-maximum)(umol*min/L) 15376(11687-17778.78) 14633(12322.8-20102.88) 14170.8(11646.17−17475.88) 18156.4(15254.9−27339.9) AUC cum 21600(umol*min/L) 0 2 0 2 Engraftment, toxicity, and TRM: Four patients had grade 2–4 aGVHD, with a cumulative incidence of 11.7% at 100 days. Two and 2 infants had grade 2 and grades 3–4 aGVHD, respectively. Neutrophil and platelet recoveries, cGVHD, and non-relapse mortality (NRM) incidences were 97%, 94%, 8.8%, and 2.9%, respectively. Relapse incidence was 5.9%. Incidence of veno-occlusive disease, hemorrhagic cystitis, and lung toxicities were 8.8%, 3%, and 6%, respectively. OS and EFS were 91% and 91%. Two infants had moderate HVOD and 1 infant had severe HVOD. Diagnoses before HSCT for the 3 patients with HVOD were Pyruvate kinase deficiency, Farber disease, and Juvenile myelomonocytic leukaemia. Two patients with HVOD were conditioned with a regimen containing cyclophosphamide and one infant with severe HVOD was conditioned with melphalan. Of the 3 patients who developed VOD, 2 were performed TDM on day 2, the fifth AUC values of these patients were 1621.2、2207.8 and 1421.4 µmol*min/L respectively. One infant with severe HVOD, initial AUC was 1335.9 µmol*min/L, dose reduction of 28.5%, the fifth AUC was 1421.4 µmol*min/L, and experienced progressive weight gain on day 2 and died on days 36 from pulmonary hemorrhage. Patients presented with abdominal pain, hyperbilirubinemia, and weight gain (2 patients), increased abdominal girth (1 infant). All patients received supportive treatment of HVOD including fluid restriction, furosemide, Ursodiol, defibrotide, and N-acetylcysteine. With a median time of follow-up post-transplant of 29 months (range: 4–70 months), thirty-one of the thirty-four patients were alive at follow up. Two infants died as a result of relapse (at day + 100 and 9 month), the primary disease of which were Acute erythroid leukemia and acute megakaryocytic leukemia. Among them, there was one JMML infant with primary implantation failure, but still survived after secondary transplantation in another hospital. Our multivariate analyses suggest that busulfan exposure can be used as a significant predictor for VOD, but not aGVHD, hemorrhagic cystitis, liver and lung injury or oral mucositis. Discussion We have described the pharmacokinetic disposition of busulfan after IV administration to 34 infants, undergoing HSCT. We observed a relation between development of HVOD and busulfan AUC in infants receiving in IV busulfan doses systemic exposure exceeded 20000µmol*min/L 17, 18 . Both infants with HVOD were underwent TDM only on day 2 or day 2 and day 3. Large interindividual and intraindividual variations in the pharmacokinetics of busulfan were evident, necessitating varying dose adjustments at day 2 to 4 of busulfan treatment. No TDM on day 1 would have been associated with the highest proportion of overexposure. Our findings demonstrate that the therapeutic window for i.v. busulfan in infants is rather narrow when used in an ablative conditioning regimen before HSCT. The mean systemic exposure (AUC) is 819.91 ± 185.56 µmol*min/L after the first dose、1261.32 ± 349.772µmol*min/L after the fifth dose and 1235.2 ± 342.69 after the ninth dose. Increased toxicity was associated with higher busulfan exposure, especially when melphalan was part of the conditioning regimen. Lung toxicity was not associated with busulfan exposure. Busulfan is associated mainly with later-onset lung toxicity, however. Given our limited follow-up period (median time of 2.5 years for the whole group), we are unable to comment on the risk of late-onset lung toxicity related to busulfan exposure. In this study, 18% day-to-day variability of busulfan clearance between the 4 days of administration was shown, which is only slightly higher than the 5–10% shown in adults 19 and the 15% in paediatric patients 5 , 20 . In addition, we showed that busulfan clearance was 27% lower at day 2 than day 1 and 12% lower at days 3–4 than at day 2. The multicenter study published by Bartelink et al 21 ., also reported a mean decrease in busulfan CL over D2–4. LongBoyle et al. reported Cl decreases by approximately 20% over time 22 . Lee et al 23 . performed an interesting analysis of individual busulfan pharmacokinetics with daily TDM performed in 20 children. Their results also showed variable profiles of CL change over the 4 days and signifcant intra-individual variability, with an individual median the percent coefficient of variation (CV) of 14.3% (range 7.7–38.7%). Our results in 34 patients over 3 days (median CV 30%; range 0.4–52%) are in agreement. Again, the average variability quantified by CV was limited, but some patients clearly exhibit unstable CL. Also, in some patients, a significant DC (≥ 20%) compared with baseline (D1) was only observed on D3, and not on D2. However, a DC was the most frequent pattern, occurring in 95% of infants. Moreover, more than 80% of those infants experienced a CL reduction ≥ 20%. Those findings have important implications for busulfan TDM. This means that performing TDM only once or twice on the first 2 days of therapy may not be sufficient to accurately estimate busulfan AUCcum and the individual dosage requirements. As parameters may be unstable, pharmacokinetic parameter estimates and dosage requirements based on early TDM may not hold true over the entire therapy. In patients who underwent TDM on each of the first 3 days of therapy there was a clear trend of decreasing CL between D1 and D3, delayed busulfan accumulation may occur in some patients and lead to unexpected and unobserved overexposure if TDM is not repeated. So, performing repeated TDM is currently the only approach to deal with this issue. Most patients in their study exhibited decreased busulfan Cl, though the authors could not identify any factors that accurately predict whether Cl will increase or decrease 5 . While the decrease in clearance deserves further study, it should be accounted for in the design of new dosing algorithms and when performing TDM. Our data show that OS and EFS may be improved by narrow targeting to a therapeutic window of busulfan exposure, necessitating repeated TDM. It is notable that despite a lack of significant correlation between high total AUC of busulfan and acute GvHD, none of the patients receiving RIC conditioning developed aGvHD; however, infants with malignant diseases receiving highly toxic BU/MEL had a high risk of developing acute GvHD or VOD, even with low total AUC of busulfan. According to pharmacokinetic results and targeted AUC, the dose was decreased in four of the 21 infants after the first AUC, the dose was increased in four of the 21 infants, and in two of four in the latter were reduced to the original dose after the fifth dose of AUC. The dose was decreased in 14 of the 31 infants after the fifth AUC, the dose was increased in only two infants, in 1 of 2 in the latter, the drug was combined with rifampicin. The mean total dosage of busulfan was 11.9 mg/kg (range: 8.0–17.7), the mean total doses was 13.36 (range:10–16). There was only one failure of engraftment. 16 infants who had a dosage modification had repeated AUC determinations after the 5th dose of i.v. busulfan. The results were in the targeted range for 15 of the 16 (Table 3 ). The mean ± sd pharmacokinetically guided adjusted dosage was 0.93 + 0.11 mg/kg (range 0.69–1.11). These data support a dosage of 0.8 mg/kg given as a 2-h intravenous infusion every 6 h for 16 doses as the initial dosage in infants, as Cremers et al 24 and Dalle et al recommended 0.8 mg/kg/dose 25 . So we recommended the initial dosage prescribed was 0.8 mg/kg to target An AUC of 720–950 µmol*min/L for infants the first dose, similarly in other infants 25–27 and 1100–1250µmol*min/L for the fifth and ninth dose, which is in line with the range in children at steady state (74 to 82 mg*h/L [4500 to 5000 µmol*min/day]) 13 . In conclusion, combined with other studies, this study demonstrates that high intra-individual variability is observed for busulfan. Therefore, TDM should be performed repeatedly over 4 days or, at a minimum, twice after the first dose and at steady state. Declarations Affiliations: Department of Hematology and Oncology, Children’s Hospital of Capital Institute of Pediatrics, No.2, Yabao Road, Chaoyang District, Beijing,100020, China. Contributions Rong Liu and Jun-hui Li designed the research; Duan-Fang Shao and Shun-qiao Feng performed the research, analyzed the data and wrote the manuscript; Jun-hui Li1, Shun-qiao Feng1, Zhao-xia Zhang, Tao Hu, Meng-ze Hu, Wei Fan, Li-tian Xuan, Di-xiao Zhong, Rui-hong Tang, Ze-liang Song, Meng-na Zhai, Dan-qing Luo, lei Zhang, Juan-juan li, Jing Cao, Yu-yang Wang, Mei Yue, Li-xiao Shi contributed to the patient recruitment, treatment and collect samples; and all authors gave final approval for the manuscript. Corresponding authors: Correspondence to Jun-hui Li, Rong Liu. Telephone:0861085695679, [email protected] Ethics declarations: Ethics approval and consent to participate; The study was conducted in accordance with the Declaration of Helsinki. Guardians and/or patients provided written informed consent before study procedures began. The protocol was approved by institutional review boards at Children’s Hospital of Capital Institute of Pediatrics. Consent for publication This manuscript has been read and approved by all the authors to publish and is not submitted or under consideration for publication elsewhere. Competing interests All authors declare that they have no competing interests. Funding This work was partly supported by grants from the youth development program of Capital Institute of Pediatrics (PY-2017-03), young backbone individual project of Beijing Excellent Talents Training Fund (2017000021469G247). Availability of data and materials: The datasets used during the current study are available from the corresponding author on reasonable request. References Choong E, Uppugunduri CRS, Marino D, Kuntzinger M, Doffey-Lazeyras F, Lo Piccolo R et al. Therapeutic Drug Monitoring of Busulfan for the Management of Pediatric Patients: Cross-Validation of Methods and Long-Term Performance. Ther Drug Monit 2018; 40 (1) : 84-92. doi: 10.1097/ftd.0000000000000468 Booth BP, Rahman A, Dagher R, Griebel D, Lennon S, Fuller D et al. Population pharmacokinetic-based dosing of intravenous busulfan in pediatric patients. J Clin Pharmacol 2007; 47 (1) : 101-111. doi: 10.1177/0091270006295789 Palmer J, McCune JS, Perales MA, Marks D, Bubalo J, Mohty M et al. Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow Transplant 2016; 22 (11) : 1915-1925. e-pub ahead of print 20160729; doi: 10.1016/j.bbmt.2016.07.013 McCune JS, Bemer MJ, Barrett JS, Scott Baker K, Gamis AS, Holford NH. Busulfan in infant to adult hematopoietic cell transplant recipients: a population pharmacokinetic model for initial and Bayesian dose personalization. Clin Cancer Res 2014; 20 (3) : 754-763. e-pub ahead of print 20131111; doi: 10.1158/1078-0432.Ccr-13-1960 Marsit H, Philippe M, Neely M, Rushing T, Bertrand Y, Ducher M et al. Intra-individual Pharmacokinetic Variability of Intravenous Busulfan in Hematopoietic Stem Cell-Transplanted Children. Clin Pharmacokinet 2020; 59 (8) : 1049-1061. doi: 10.1007/s40262-020-00877-z Briki M, André P, Thoma Y, Widmer N, Wagner AD, Decosterd LA et al. Precision Oncology by Point-of-Care Therapeutic Drug Monitoring and Dosage Adjustment of Conventional Cytotoxic Chemotherapies: A Perspective. Pharmaceutics 2023; 15 (4). e-pub ahead of print 20230419; doi: 10.3390/pharmaceutics15041283 Nguyen L, Fuller D, Lennon S, Leger F, Puozzo C. I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transplant 2004; 33 (10) : 979-987. doi: 10.1038/sj.bmt.1704446 Shao DF, Li JH, Hu T, Zhang ZX, Zhang L, Li JJ et al. Clinical outcomes of individualized busulfan-dosing in hematopoietic stem cell transplantation in Chinese children undergoing with therapeutic drug monitoring. Bone Marrow Transplant 2022; 57 (3) : 473-478. e-pub ahead of print 20220117; doi: 10.1038/s41409-021-01545-x Grochow LB. Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens. Semin Oncol 1993; 20 (4 Suppl 4) : 18-25; quiz 26. Lombardi LR, Kanakry CG, Zahurak M, Durakovic N, Bolaños-Meade J, Kasamon YL et al. Therapeutic drug monitoring for either oral or intravenous busulfan when combined with pre- and post-transplantation cyclophosphamide. Leuk Lymphoma 2016; 57 (3) : 666-675. e-pub ahead of print 20151012; doi: 10.3109/10428194.2015.1071488 Alsultan A, Albassam AA, Alturki A, Alsultan A, Essa M, Almuzzaini B, Alfadhel S. Can First-Dose Therapeutic Drug Monitoring Predict the Steady State Area Under the Blood Concentration-Time Curve of Busulfan in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation? Front Pediatr 2022; 10: 834773. e-pub ahead of print 20220407; doi: 10.3389/fped.2022.834773 Malär R, Sjöö F, Rentsch K, Hassan M, Güngör T. Therapeutic drug monitoring is essential for intravenous busulfan therapy in pediatric hematopoietic stem cell recipients. Pediatr Transplant 2011; 15 (6) : 580-588. e-pub ahead of print 20110708; doi: 10.1111/j.1399-3046.2011.01529.x Bartelink IH, Bredius RGM, Belitser SV, Suttorp MM, Bierings M, Knibbe CAJ et al. Association between Busulfan Exposure and Outcome in Children Receiving Intravenous Busulfan before Hematologic Stem Cell Transplantation. Biology of Blood and Marrow Transplantation 2009; 15 (2) : 231-241. doi: 10.1016/j.bbmt.2008.11.022 Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA, Thomas ED. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6 (10) : 1562-1568. doi: 10.1200/jco.1988.6.10.1562 McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993; 118 (4) : 255-267. doi: 10.7326/0003-4819-118-4-199302150-00003 Martino R, Romero P, Subirá M, Bellido M, Altés A, Sureda A et al. Comparison of the classic Glucksberg criteria and the IBMTR Severity Index for grading acute graft-versus-host disease following HLA-identical sibling stem cell transplantation. International Bone Marrow Transplant Registry. Bone Marrow Transplant 1999; 24 (3) : 283-287. doi: 10.1038/sj.bmt.1701899 Qureshi A, Marshall L, Lancaster D. Defibrotide in the prevention and treatment of veno-occlusive disease in autologous and allogeneic stem cell transplantation in children. Pediatr Blood Cancer 2008; 50 (4) : 831-832. doi: 10.1002/pbc.21425 Geddes M, Kangarloo SB, Naveed F, Quinlan D, Chaudhry MA, Stewart D et al. High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen. Biol Blood Marrow Transplant 2008; 14 (2) : 220-228. doi: 10.1016/j.bbmt.2007.10.028 Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 2008; 48: 303-332. doi: 10.1146/annurev.pharmtox.48.113006.094708 Bartelink IH, Boelens JJ, Bredius RG, Egberts AC, Wang C, Bierings MB et al. Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing. Clin Pharmacokinet 2012; 51 (5) : 331-345. doi: 10.2165/11598180-000000000-00000 Bartelink IH, Lalmohamed A, van Reij EM, Dvorak CC, Savic RM, Zwaveling J et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol 2016; 3 (11) : e526-e536. e-pub ahead of print 20161013; doi: 10.1016/s2352-3026(16)30114-4 Long-Boyle JR, Savic R, Yan S, Bartelink I, Musick L, French D et al. Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use. Ther Drug Monit 2015; 37 (2) : 236-245. doi: 10.1097/ftd.0000000000000131 Lee JW, Kang HJ, Lee SH, Yu K-S, Kim NH, Yuk YJ et al. Highly Variable Pharmacokinetics of Once-Daily Intravenous Busulfan When Combined with Fludarabine in Pediatric Patients: Phase I Clinical Study for Determination of Optimal Once-Daily Busulfan Dose Using Pharmacokinetic Modeling. Biology of Blood and Marrow Transplantation 2012; 18 (6) : 944-950. doi: 10.1016/j.bbmt.2011.11.025 Cremers S, Schoemaker R, Bredius R, den Hartigh J, Ball L, Twiss I et al. Pharmacokinetics of intravenous busulfan in children prior to stem cell transplantation. Br J Clin Pharmacol 2002; 53 (4) : 386-389. doi: 10.1046/j.1365-2125.2002.01555.x Dalle JH, Wall D, Theoret Y, Duval M, Shaw L, Larocque D et al. Intravenous busulfan for allogeneic hematopoietic stem cell transplantation in infants: clinical and pharmacokinetic results. Bone Marrow Transplant 2003; 32 (7) : 647-651. doi: 10.1038/sj.bmt.1704209 Ansari M, Théoret Y, Rezgui MA, Peters C, Mezziani S, Desjean C et al. Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematopoietic stem cell transplantation. Ther Drug Monit 2014; 36 (1) : 93-99. doi: 10.1097/FTD.0b013e3182a04fc7 Baker KS, Bostrom B, DeFor T, Ramsay NK, Woods WG, Blazar BR. Busulfan pharmacokinetics do not predict relapse in acute myeloid leukemia. Bone Marrow Transplant 2000; 26 (6) : 607-614. doi: 10.1038/sj.bmt.1702590 Additional Declarations No competing interests reported. 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. 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14:38:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5251996/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5251996/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81013363,"identity":"71395634-4ec1-47a4-bbef-d67c4a7cccbd","added_by":"auto","created_at":"2025-04-21 08:35:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":243865,"visible":true,"origin":"","legend":"\u003cp\u003eApproximate AUC\u003csub\u003ecum\u003c/sub\u003e of Bu in relation to underlying disease.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5251996/v1/b1cdf018059d2210333b9a21.png"},{"id":81012112,"identity":"f625db27-3d9e-40d4-958f-c9316eb283a4","added_by":"auto","created_at":"2025-04-21 08:27:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":195087,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual changes in busulfan clearance between the first and second day of therapy(n=20)\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5251996/v1/562eeaf2f749c897f9718220.png"},{"id":82360792,"identity":"9bd01f36-5e82-4cd2-8e6c-868c06f0c350","added_by":"auto","created_at":"2025-05-09 11:39:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1618905,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5251996/v1/03868d6a-4283-4035-a3a8-50f01408919b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Precision dosing of intravenous busulfan in infants patients undergoing bone marrow transplantation in China","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChildren may differ from adults with regards to drug pharmacokinetics, both in response to treatment (efficacy) and their susceptibility to side effects (safety). Variability in pharmacokinetics is one factor which alters drug exposure, and this in turn might explain differences in the (un)wanted responses (pharmacodynamics) between children. Characterization of variability in pharmacokinetics between neonates, infants, children and adolescents is therefore important, especially for drugs with a small therapeutic window such as busulfan (BSF). Commonly used as part of the conditioning regimen prior to hematopoietic stem cells transplantation (HSCT), BSF-based treatments represent a preferred alternative to total body irradiation (TBI), especially in pediatric patients\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Typically, BSF is administered over 4 days in the form of 2-hour (h) infusions every 6h. The US FDA labeling recommends that the initial dose is based on body weight. The recommended dose is 1.1 mg/kg for patients\u0026thinsp;\u0026le;\u0026thinsp;12 kg and 0.8 mg/kg for patients\u0026thinsp;\u0026ge;\u0026thinsp;12 kg with an acceptable BU AUC being 900 to 1350\u0026thinsp;\u0026plusmn;\u0026thinsp;5% \u0026micro;molar \u0026times; minute\u003csup\u003e2\u003c/sup\u003e (C\u003csub\u003eSS\u003c/sub\u003e = 650 ng/mL to 924 ng/mL). The EMA algorithm is more complicated because it has 5 dose cohorts (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) that are based on actual body weight to achieve a BU AUC of 900 \u0026micro;molar \u0026times; minute to 1500 \u0026micro;molar \u0026times; minute (C\u003csub\u003eSS\u003c/sub\u003e = 650 ng/mL to 1026 ng/mL).\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\u003e Busulfan manufacturer dosing guidelines\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient weight(kg)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIV busulfan dose(mg/kg/dose)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9 to\u0026lt;16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16 to\u0026lt;23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23 to\u0026lt;34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThese 2 different dosing recommendations were based on popPK modeling\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. A greater proportion of patients achieve the target exposure when using EMA dosing (70%) than when using the FDA dosing (57%), based on simulations using a popPK model built using data from 1610 HCT recipients (92% of whom were children)\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Thus, the EMA dosing is recommended. Intravenous (IV) busulfan shows large pharmacokinetic (PK) variability between children and the optimal exposure range in children has not been precisely defined\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Significant busulfan intra-individual variability may occur in children who receive a HSCT and is hardly predictable. Indeed, patients undergoing BSF therapy typically experience a significant decrease in drug clearance (CLBSF) shortly after treatment initiation\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, which complicates the execution of TDM. Performing TDM repeatedly over therapy appears to be the best way to accurately estimate busulfan exposure and perform precision dosing\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. However, the optimal dose, optimal AUC target, and dosing schedule of i.v. busulfan in children remain undecided.\u003c/p\u003e \u003cp\u003eWe conducted a retrospective analysis of a cohort of infant patients who underwent HSCT and had a wide range of exposure to busulfan. The aim was to establish the optimal busulfan exposure in relation to efficacy and toxicity.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003ePatients:\u003c/p\u003e \u003cp\u003eThirty-four infants with a median age of 8.5 months (range, 5 to 12 months) were included in the pharmacokinetic study, which was approved by the institutional review board of the Hospital of Capital Institute of Pediatrics. Informed consent was obtained from parents of all patients. All patients had indwelling central venous catheters from which blood samples were obtained. Clinical data for the thirty-four infants are listed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\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\u003ePatient Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge/sex\u003c/p\u003e \u003cp\u003e(m)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeight\u003c/p\u003e \u003cp\u003e(kg)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDisease\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGVHD prophylaxis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDonor type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eTotal doses\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTotal Dosage of Busulfan(mg/kg)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMAL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCLAG\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;Mel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;MTX\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMRD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSCID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLU\u0026thinsp;+\u0026thinsp;CTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.5/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePKD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLU\u0026thinsp;+\u0026thinsp;CTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePTcy\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e13.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAML\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIDA\u0026thinsp;+\u0026thinsp;Ara-c\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;CTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e16.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;PTcy\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMRD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e13.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;PTcy\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMRD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e16.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAEL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCL\u0026thinsp;+\u0026thinsp;Ara\u0026thinsp;+\u0026thinsp;IDA\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;Cy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e17.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAML\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCLAG\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;Cy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFLu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e 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colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;CTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.5/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e 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colname=\"c5\"\u003e \u003cp\u003eAra-c\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;CTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMPS IIIa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;CTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e17.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;CTX\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;CTX\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;CTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.5/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;PTcy\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMRD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e16.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.5/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFLu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePTcy\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFHL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFLu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;TT\u0026thinsp;+\u0026thinsp;VP16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePTcy\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMRD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.5/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eJMML\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAra\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;Bu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e16.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.5/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHIGM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;PTcy\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e11.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.8/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;CTX\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAML\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;CTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.8/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCGD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;PTcy\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMRD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCGD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;CTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;PTcy\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMRD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e17.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.8/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCGD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBu\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;CTX\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e16.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.4/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eALL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAra\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;Bu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.5/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eJMML\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFLu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;Mel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;PTcy\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e11.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.6/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eJMML\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAra\u0026thinsp;+\u0026thinsp;FLu\u0026thinsp;+\u0026thinsp;Bu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePTcy\u0026thinsp;+\u0026thinsp;CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.5/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAML-M7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCLAG\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;Cy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATG\u0026thinsp;+\u0026thinsp;CsA\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMRD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eAbbreviations: MAL, acute mixed leukemia; SCID, X-linked severe immunodeficiency; PKD, Pyruvate kinase deficiency; AML, acute myeloid leukemia; FD, Farber disease ; WAS, Wiskott-Aldrich syndrome; AEL, Acute erythroid leukemia; PID, primary immune deficiency ; MPS, Mucopolysaccharidosis; FHL, familialhemophagocytic syndrome; JMML, Juvenile myelomonocytic leukaemia; HIGM, IgM increased immune deficiency; CGD, chronic granulomatous disease; ALL, Acute Lymphocytic Leukemia; Bu, busulfan; CPM, cyclophosphamide; L-PAM, melphalan; TTP, thiotepa, MMUD/MMRD,\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003emismatched unrelated/related donor; MSD, matched sibling donor; MUD, matched unrelated donor; MMCB, mismatched cord blood\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBusulfan Concentration Data:\u003c/p\u003e \u003cp\u003eBusulfan was administered over 3 or 4 consecutive days as a 2-h infusion administered every 6h in most patients. The initial dose ranged from 0.75 to 1.2 mg/kg, depending on the patient\u0026rsquo;s body weight and disease, in accordance with the European summary of product characteristics and our past experience\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Bu was preferentially utilized for workday admissions as PK\u0026rsquo;s were not available for two consecutive days (weekend PK\u0026rsquo;s were not routinely available during this time period). Because, the high intra-individual variability and possible time-dependent changes in clearance (Cl) during elimination, TDM of busulfan and dose individualization were performed for all patients in order to achieve the target IV BU exposure (AUC) is the first-dose AUC with an acceptable range of 720 to 950\u0026thinsp;\u0026plusmn;\u0026thinsp;5% \u0026micro;molar \u0026times; minute and the fifth-dose AUC 1125\u0026thinsp;\u0026plusmn;\u0026thinsp;5% \u0026micro;molar \u0026times; minute after every 6 hour (Q6H) dosing. This target Bu AUC was chosen based on original studies by Grochow and colleagues as well as our historical experience\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. The blood samples were obtained prior to infusion and at 60, 120, 150, 180, 240 and 360 min (trough level) post-infusion. The next Bu dose was not administered until the 360 min blood sample had been obtained. Blood samples were drawn from the catheter lumen that was not used for dose administration. TDM could be subsequently performed again with the same sampling scheme during the last 2 or 3 days of therapy in some patients, in order to control the observed AUC and adjust the dose again if necessary. The decision to repeat TDM was taken at the physician\u0026rsquo;s discretion. When the first-dose and fifth-dose AUC was within the target range, no repeat PK analysis was performed. If a patient\u0026rsquo;s first-dose or fifth-dose AUC was outside the target range, the dosage was adjusted on the 5th or 9th dose and repeat PK analysis was performed as needed to achieve the target AUC. When adjustments were made they were typically a 15\u0026ndash;35% decrease or up to a 20% increase from the prior dosage. Total Bu exposure, described by an estimated total cumulative AUC, was retrospectively calculated as previously published by Bartelink and colleagues\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEndpoints and definitions:\u003c/p\u003e \u003cp\u003eThe main study endpoints were event-free survival (EFS) and overall survival (OS) after HSCT, with a follow up of at least 4 months. EFS was defined as alive with engraftment (\u0026gt;\u0026thinsp;95% chimerism) and without evident relapse in those children who underwent transplantation for malignant disease. EFS was calculated from the time of transplant until death, relapse or graft failure, whichever occurred first. OS was the time between transplantation and death of any causes. Primary graft failure was defined as failure to achieve a sustained absolute neutrophil count of \u0026ge;\u0026thinsp;500/\u0026micro;L in the absence of persistent or relapsed disease. Regarding acute toxicity was evaluated according to the Bearman score\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. VOD was assessed using both the Baltimore and McDonald criteria\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. aGVHD was diagnosed and graded according to the criteria of Glucksberg et al\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Chimerism\u0026thinsp;\u0026gt;\u0026thinsp;95% was considered full donor chimerism; donor chimerism\u0026thinsp;\u0026gt;\u0026thinsp;10% and \u0026lt;\u0026thinsp;95% was considered mixed chimerism; graft rejection was defined as donor chimerism\u0026thinsp;\u0026lt;\u0026thinsp;10%.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis:\u003c/h2\u003e \u003cp\u003eOverall survival (OS) and DFS probabilities were estimated using the Kaplan-Meier method. The Mann-Whitney U test was used for continuous variables, while the chi-squared test was used for categorical variables. The logistic regression model was used to relate Bu AUC, donor source, GVHD prophylaxis and other patient characteristics (weight, age, and disease) to probability of engraftment or toxicity. Significant difference was set at a level of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. SPSS 19.0 (Mathsoft, Seattle, WA, USA) was used for data analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes patient, disease, and transplantation characteristics of 34 infants, 23 (67.6%) were below 9kg and 26 (76.5%) were male. Median age was 8.5 (5\u0026ndash;12) months, average\u0026thinsp;\u0026plusmn;\u0026thinsp;SD weight was 8.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.48 kg, and average\u0026thinsp;\u0026plusmn;\u0026thinsp;SD dose received was 0.93\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11 mg/kg; \u0026lt;9 kg, 0.75\u0026ndash;1.1 mg/kg initial per dose (mean dose 0.91mg/kg, mean 13.45 doses, mean total dosage 12.35mg/kg ); 9\u0026ndash;12 kg, 0.82\u0026ndash;1.2 mg/kg initial per dose (mean dose 0.96mg/kg, mean 13 doses, mean total dose 12.84mg/kg). We also obtained samples at steady state for 33 infants. Among these 33 infants, no dose adjustments were made for seven infants, the dose was increased for six patients, and the dose was decreased for 20 patients. Twelve (35%) infants had a malignant disease and nineteen (58%) were immunodeficiency related diseases. Eleven infants received a graft from a related donor and 5 from an unrelated donor; 18 infants received a CBT. Twenty-nine (85%) patients received IV Bu\u0026thinsp;+\u0026thinsp;FIu as conditioning. All patients received CNI as GVHD prophylaxis associated with MMF (94%) or PTcy (35%). The median number of CD34\u0026thinsp;+\u0026thinsp;cells infused was 8.5 *10\u003csup\u003e6\u003c/sup\u003e/kg for bone marrow\u0026thinsp;+\u0026thinsp;peripheral blood/peripheral blood stem cell and 4.3 *10\u003csup\u003e5\u003c/sup\u003e/kg for CBT.\u003c/p\u003e \u003cp\u003eBusulfan Dose and Pharmacokinetics:\u003c/p\u003e \u003cp\u003ePharmacokinetic parameters after the first, fifth and ninth doses in 21, 31 and 16 infants are given in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. There were wide inter-individual variations in terms of busulfan disposition with maximal concentration ranging from 794.1 to 2229.0 ng/ml at steady state of the fifth dose. The mean systemic exposure(AUC) is 819.91\u0026thinsp;\u0026plusmn;\u0026thinsp;185.56 \u0026micro;mol*min/L after the first dose、1261.32\u0026thinsp;\u0026plusmn;\u0026thinsp;349.772\u0026micro;mol*min/L after the fifth dose and 1235.2\u0026thinsp;\u0026plusmn;\u0026thinsp;342.69 after the ninth dose. The study population exhibit a wide range in total AUC, from 11646.1 to 27339.9 \u0026micro;mol*min/L, we were unable to prove a correlation between total busulfan exposure and underlying disease (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Large inter-individual and intra-individual variations in the pharmacokinetics of busulfan were evident, necessitating varying dose adjustments at day\u0026thinsp;+\u0026thinsp;2 to +\u0026thinsp;4 of busulfan treatment. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e displays the individual changes in busulfan CL in those 20 infants. For all parameters, both increase and decrease occurs. The average magnitude of the changes was limited, but large variability was observed. A majority of patients experienced a decrease in busulfan CL. Regarding CL, the mean value was signifcantly decreased on D2 compared with D1 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with a mean change of \u0026minus;\u0026thinsp;26.9%. The majority of patients (n\u0026thinsp;=\u0026thinsp;19 [95%]) experienced a decrease in CL(DC) between D1 and D2, with a mean decrease of \u0026minus;\u0026thinsp;28.5% (range\u0026thinsp;\u0026minus;\u0026thinsp;40.1 to \u0026minus;\u0026thinsp;9.7%), including 3, and 16 infants with a decrease between 9.7% and 20%, and \u0026ge;\u0026thinsp;20%, respectively. One infant (5%) experienced an increase in CL, with a change of +\u0026thinsp;3.9%. Various TDM strategies and effect on exposure are shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. In infants who underwent TDM on D1, D2, and D3, the proportion of overexposure was the lowest (0/9). Performing TDM only on D2 appears insufficient to minimize overexposure, the rate of which would have been 28.5% (2/7). By contrast, performing TDM on D1 and D2 appears more effective in reducing inter-patient variability in AUC\u003csub\u003ecum\u003c/sub\u003e and prevent overexposure, as the rate would have been similar to the 3-day TDM strategy (0/11).\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 After the First、Fifth、Ninth and Thirteenth Doses of Busulfan\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"14\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eFirst Dosing\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c8\" namest=\"c5\"\u003e \u003cp\u003eFifth Dosing\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c13\" namest=\"c9\"\u003e \u003cp\u003eNinth Dosing\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003eThirteenth\u003c/p\u003e \u003cp\u003eDosing\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC\u003csub\u003emin\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;6h\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(umol*min/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFirst dosage\u003c/p\u003e \u003cp\u003e(mg/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC\u003csub\u003emin\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;6h\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(umol*min/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eFifth dosage\u003c/p\u003e \u003cp\u003e(mg/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eC\u003csub\u003emin\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;6h\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(umol*min/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eNinth dosage\u003c/p\u003e \u003cp\u003e(mg/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eThirteenth dosage\u003c/p\u003e \u003cp\u003e(mg/kg)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\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\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1091.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\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\u003e1821\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e953\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1993.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1047\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e468\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1084.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e 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colname=\"c5\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1513\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e482\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1284.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e 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colname=\"c12\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\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\u003e1698\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e646\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e 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align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1348\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e508\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1316.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1235\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e565\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1207.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.947\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e 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colname=\"c12\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e415\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1015.5\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\u003e1536\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e531\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e 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align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1480\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e573\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1416.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e 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colname=\"c12\"\u003e \u003cp\u003e926.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e773\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e554\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e837.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e745\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e 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colname=\"c12\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e705\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e725.87\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\u003e991\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e605\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1127.95\u003c/p\u003e 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align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e382\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1002.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1284\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e548\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e964.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1446\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e502\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e 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align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e887\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e341\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e961.084\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e905\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e352\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e911.328\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e905\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e294\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e790.7\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\u003e1344\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e384\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1135.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e 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align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1682\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e829\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1755.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1238\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e697\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1370.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e 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colname=\"c12\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e747\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e452\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e813.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e611\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e 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colname=\"c12\"\u003e \u003cp\u003e1300.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e29*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\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\u003e659\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e265\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e672.22\u003c/p\u003e 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align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e794.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e839.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e426\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1189.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e 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align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1002.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.583\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e838\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1099.7\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\u003e1048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e436\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1174.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\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\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1026.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\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\u003e1136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e473\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1066.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e487\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e530.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e794.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e830.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e892\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e322\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e911.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1294\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e838\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1335.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2229.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1211.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2207.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2899\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e958\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e2279.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e903.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e384.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e819.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1294.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e562.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1261.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1267.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e538.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1235.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e222.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e149.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e185.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e352.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e218.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e349.772\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e508.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e196.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e342.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003eND Not determined, NA Not available, *Combined with rifampicin\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \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\u003eVarious therapeutic drug monitoring strategies and predicted exposure in 32 infants who underwent therapeutic drug monitoring on different days.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTDM on D1, D2 and D3 (actual strategy)(n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTDM on D2 (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTDM on D1 and D2 (n\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTDM on D2 and D3 (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean AUC\u003csub\u003ecum\u003c/sub\u003e \u0026plusmn;SD(umol*min/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15028.93\u0026thinsp;\u0026plusmn;\u0026thinsp;2482.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15423.18\u0026thinsp;\u0026plusmn;\u0026thinsp;3149.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14172.52\u0026thinsp;\u0026plusmn;\u0026thinsp;1791.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19363.01\u0026thinsp;\u0026plusmn;\u0026thinsp;4783.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian AUC\u003csub\u003ecum\u003c/sub\u003e (minimum-maximum)(umol*min/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15376(11687-17778.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14633(12322.8-20102.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14170.8(11646.17\u0026minus;17475.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18156.4(15254.9\u0026minus;27339.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003ecum\u003c/sub\u003e\u0026lt;14400(umol*min/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003ecum\u003c/sub\u003e\u0026gt;21600(umol*min/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eEngraftment, toxicity, and TRM:\u003c/p\u003e \u003cp\u003eFour patients had grade 2\u0026ndash;4 aGVHD, with a cumulative incidence of 11.7% at 100 days. Two and 2 infants had grade 2 and grades 3\u0026ndash;4 aGVHD, respectively. Neutrophil and platelet recoveries, cGVHD, and non-relapse mortality (NRM) incidences were 97%, 94%, 8.8%, and 2.9%, respectively. Relapse incidence was 5.9%. Incidence of veno-occlusive disease, hemorrhagic cystitis, and lung toxicities were 8.8%, 3%, and 6%, respectively. OS and EFS were 91% and 91%. Two infants had moderate HVOD and 1 infant had severe HVOD. Diagnoses before HSCT for the 3 patients with HVOD were Pyruvate kinase deficiency, Farber disease, and Juvenile myelomonocytic leukaemia. Two patients with HVOD were conditioned with a regimen containing cyclophosphamide and one infant with severe HVOD was conditioned with melphalan. Of the 3 patients who developed VOD, 2 were performed TDM on day 2, the fifth AUC values of these patients were 1621.2、2207.8 and 1421.4 \u0026micro;mol*min/L respectively. One infant with severe HVOD, initial AUC was 1335.9 \u0026micro;mol*min/L, dose reduction of 28.5%, the fifth AUC was 1421.4 \u0026micro;mol*min/L, and experienced progressive weight gain on day 2 and died on days 36 from pulmonary hemorrhage. Patients presented with abdominal pain, hyperbilirubinemia, and weight gain (2 patients), increased abdominal girth (1 infant). All patients received supportive treatment of HVOD including fluid restriction, furosemide, Ursodiol, defibrotide, and N-acetylcysteine. With a median time of follow-up post-transplant of 29 months (range: 4\u0026ndash;70 months), thirty-one of the thirty-four patients were alive at follow up. Two infants died as a result of relapse (at day\u0026thinsp;+\u0026thinsp;100 and 9 month), the primary disease of which were Acute erythroid leukemia and acute megakaryocytic leukemia. Among them, there was one JMML infant with primary implantation failure, but still survived after secondary transplantation in another hospital. Our multivariate analyses suggest that busulfan exposure can be used as a significant predictor for VOD, but not aGVHD, hemorrhagic cystitis, liver and lung injury or oral mucositis.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe have described the pharmacokinetic disposition of busulfan after IV administration to 34 infants, undergoing HSCT. We observed a relation between development of HVOD and busulfan AUC in infants receiving in IV busulfan doses systemic exposure exceeded 20000\u0026micro;mol*min/L\u003csup\u003e17, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Both infants with HVOD were underwent TDM only on day 2 or day 2 and day 3. Large interindividual and intraindividual variations in the pharmacokinetics of busulfan were evident, necessitating varying dose adjustments at day 2 to 4 of busulfan treatment. No TDM on day 1 would have been associated with the highest proportion of overexposure. Our findings demonstrate that the therapeutic window for i.v. busulfan in infants is rather narrow when used in an ablative conditioning regimen before HSCT. The mean systemic exposure (AUC) is 819.91\u0026thinsp;\u0026plusmn;\u0026thinsp;185.56 \u0026micro;mol*min/L after the first dose、1261.32\u0026thinsp;\u0026plusmn;\u0026thinsp;349.772\u0026micro;mol*min/L after the fifth dose and 1235.2\u0026thinsp;\u0026plusmn;\u0026thinsp;342.69 after the ninth dose. Increased toxicity was associated with higher busulfan exposure, especially when melphalan was part of the conditioning regimen. Lung toxicity was not associated with busulfan exposure. Busulfan is associated mainly with later-onset lung toxicity, however. Given our limited follow-up period (median time of 2.5 years for the whole group), we are unable to comment on the risk of late-onset lung toxicity related to busulfan exposure.\u003c/p\u003e \u003cp\u003eIn this study, 18% day-to-day variability of busulfan clearance between the 4 days of administration was shown, which is only slightly higher than the 5\u0026ndash;10% shown in adults\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e and the 15% in paediatric patients\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. In addition, we showed that busulfan clearance was 27% lower at day 2 than day 1 and 12% lower at days 3\u0026ndash;4 than at day 2. The multicenter study published by Bartelink et al\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e., also reported a mean decrease in busulfan CL over D2\u0026ndash;4. LongBoyle et al. reported Cl decreases by approximately 20% over time\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Lee et al\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. performed an interesting analysis of individual busulfan pharmacokinetics with daily TDM performed in 20 children. Their results also showed variable profiles of CL change over the 4 days and signifcant intra-individual variability, with an individual median the percent coefficient of variation (CV) of 14.3% (range 7.7\u0026ndash;38.7%). Our results in 34 patients over 3 days (median CV 30%; range 0.4\u0026ndash;52%) are in agreement. Again, the average variability quantified by CV was limited, but some patients clearly exhibit unstable CL. Also, in some patients, a significant DC (\u0026ge;\u0026thinsp;20%) compared with baseline (D1) was only observed on D3, and not on D2. However, a DC was the most frequent pattern, occurring in 95% of infants. Moreover, more than 80% of those infants experienced a CL reduction\u0026thinsp;\u0026ge;\u0026thinsp;20%.\u003c/p\u003e \u003cp\u003eThose findings have important implications for busulfan TDM. This means that performing TDM only once or twice on the first 2 days of therapy may not be sufficient to accurately estimate busulfan AUCcum and the individual dosage requirements. As parameters may be unstable, pharmacokinetic parameter estimates and dosage requirements based on early TDM may not hold true over the entire therapy. In patients who underwent TDM on each of the first 3 days of therapy there was a clear trend of decreasing CL between D1 and D3, delayed busulfan accumulation may occur in some patients and lead to unexpected and unobserved overexposure if TDM is not repeated. So, performing repeated TDM is currently the only approach to deal with this issue. Most patients in their study exhibited decreased busulfan Cl, though the authors could not identify any factors that accurately predict whether Cl will increase or decrease\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. While the decrease in clearance deserves further study, it should be accounted for in the design of new dosing algorithms and when performing TDM. Our data show that OS and EFS may be improved by narrow targeting to a therapeutic window of busulfan exposure, necessitating repeated TDM.\u003c/p\u003e \u003cp\u003eIt is notable that despite a lack of significant correlation between high total AUC of busulfan and acute GvHD, none of the patients receiving RIC conditioning developed aGvHD; however, infants with malignant diseases receiving highly toxic BU/MEL had a high risk of developing acute GvHD or VOD, even with low total AUC of busulfan. According to pharmacokinetic results and targeted AUC, the dose was decreased in four of the 21 infants after the first AUC, the dose was increased in four of the 21 infants, and in two of four in the latter were reduced to the original dose after the fifth dose of AUC. The dose was decreased in 14 of the 31 infants after the fifth AUC, the dose was increased in only two infants, in 1 of 2 in the latter, the drug was combined with rifampicin. The mean total dosage of busulfan was 11.9 mg/kg (range: 8.0\u0026ndash;17.7), the mean total doses was 13.36 (range:10\u0026ndash;16). There was only one failure of engraftment. 16 infants who had a dosage modification had repeated AUC determinations after the 5th dose of i.v. busulfan. The results were in the targeted range for 15 of the 16 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The mean\u0026thinsp;\u0026plusmn;\u0026thinsp;sd pharmacokinetically guided adjusted dosage was 0.93\u0026thinsp;+\u0026thinsp;0.11 mg/kg (range 0.69\u0026ndash;1.11). These data support a dosage of 0.8 mg/kg given as a 2-h intravenous infusion every 6 h for 16 doses as the initial dosage in infants, as Cremers et al\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e and Dalle et al recommended 0.8 mg/kg/dose\u003csup\u003e25\u003c/sup\u003e. So we recommended the initial dosage prescribed was 0.8 mg/kg to target An AUC of 720\u0026ndash;950 \u0026micro;mol*min/L for infants the first dose, similarly in other infants\u003csup\u003e25\u0026ndash;27\u003c/sup\u003e and 1100\u0026ndash;1250\u0026micro;mol*min/L for the fifth and ninth dose, which is in line with the range in children at steady state (74 to 82 mg*h/L [4500 to 5000 \u0026micro;mol*min/day])\u003csup\u003e13\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn conclusion, combined with other studies, this study demonstrates that high intra-individual variability is observed for busulfan. Therefore, TDM should be performed repeatedly over 4 days or, at a minimum, twice after the first dose and at steady state.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAffiliations:\u003c/p\u003e\n\u003cp\u003eDepartment of Hematology and Oncology, Children\u0026rsquo;s Hospital of Capital Institute of Pediatrics, No.2, Yabao Road, Chaoyang District, Beijing,100020, China.\u003c/p\u003e\n\u003cp\u003eContributions\u003c/p\u003e\n\u003cp\u003eRong Liu and Jun-hui Li designed the research; Duan-Fang Shao and Shun-qiao Feng performed the research, analyzed the data and wrote the manuscript; Jun-hui Li1, Shun-qiao Feng1, Zhao-xia Zhang, Tao Hu, Meng-ze Hu, Wei Fan, Li-tian Xuan, Di-xiao Zhong, Rui-hong Tang, Ze-liang Song, Meng-na Zhai, Dan-qing Luo, lei Zhang, Juan-juan li, Jing Cao, Yu-yang Wang, Mei Yue, Li-xiao Shi contributed to the patient recruitment, treatment and collect samples; and all authors gave final approval for the manuscript.\u003c/p\u003e\n\u003cp\u003eCorresponding authors:\u003c/p\u003e\n\u003cp\u003eCorrespondence to Jun-hui Li, Rong Liu.\u003c/p\u003e\n\u003cp\u003eTelephone:0861085695679,[email protected]\u003c/p\u003e\n\u003cp\u003eEthics declarations:\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate;\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki. Guardians and/or patients provided written informed consent before study procedures began. The protocol was approved by institutional review boards at Children\u0026rsquo;s Hospital of Capital Institute of Pediatrics.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eThis manuscript has been read and approved by all the authors to publish and is not submitted or under consideration for publication elsewhere.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was partly supported by grants from the youth development program of Capital Institute of Pediatrics (PY-2017-03), young backbone individual project of Beijing Excellent Talents Training Fund (2017000021469G247).\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials:\u003c/p\u003e\n\u003cp\u003eThe datasets used during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eChoong E, Uppugunduri CRS, Marino D, Kuntzinger M, Doffey-Lazeyras F, Lo Piccolo R\u003cem\u003e et al.\u003c/em\u003e Therapeutic Drug Monitoring of Busulfan for the Management of Pediatric Patients: Cross-Validation of Methods and Long-Term Performance. \u003cem\u003eTher Drug Monit \u003c/em\u003e2018; \u003cstrong\u003e40\u003c/strong\u003e(1)\u003cstrong\u003e: \u003c/strong\u003e84-92. doi: 10.1097/ftd.0000000000000468\u003c/li\u003e\n \u003cli\u003eBooth BP, Rahman A, Dagher R, Griebel D, Lennon S, Fuller D\u003cem\u003e et al.\u003c/em\u003e Population pharmacokinetic-based dosing of intravenous busulfan in pediatric patients. \u003cem\u003eJ Clin Pharmacol \u003c/em\u003e2007; \u003cstrong\u003e47\u003c/strong\u003e(1)\u003cstrong\u003e: \u003c/strong\u003e101-111. doi: 10.1177/0091270006295789\u003c/li\u003e\n \u003cli\u003ePalmer J, McCune JS, Perales MA, Marks D, Bubalo J, Mohty M\u003cem\u003e et al.\u003c/em\u003e Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. \u003cem\u003eBiol Blood Marrow Transplant \u003c/em\u003e2016; \u003cstrong\u003e22\u003c/strong\u003e(11)\u003cstrong\u003e: \u003c/strong\u003e1915-1925. e-pub ahead of print 20160729; doi: 10.1016/j.bbmt.2016.07.013\u003c/li\u003e\n \u003cli\u003eMcCune JS, Bemer MJ, Barrett JS, Scott Baker K, Gamis AS, Holford NH. 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Busulfan pharmacokinetics do not predict relapse in acute myeloid leukemia. \u003cem\u003eBone Marrow Transplant \u003c/em\u003e2000; \u003cstrong\u003e26\u003c/strong\u003e(6)\u003cstrong\u003e: \u003c/strong\u003e607-614. doi: 10.1038/sj.bmt.1702590\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":"","lastPublishedDoi":"10.21203/rs.3.rs-5251996/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5251996/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eVeno-occlusive disease (VOD) is a severe adverse reaction to busulfan-containing regimens used in the preparation of children for hematopoietic stem cell transplantation (HSCT). We previously found that the youngest children have a greater risk of VOD, and a high busulfan C\u003csub\u003emax\u003c/sub\u003e is more likely to occur after the first two doses. We conducted a retrospective pharmacokinetic analysis of IV (intravenous) busulfan in infants undergoing a hematopoietic stem cell transplantation (HSCT) and described its relation to transplantation outcomes. Thirty-four infants (median age, 8.5 months) underwent HSCT at The Hospital of Capital Institute of Pediatrics from October 2018 through April 2024 and received IV busulfan every 6 hour (h) as part of their conditioning regimen. Initial busulfan doses were based on actual patient weight: \u0026lt;9 kg, 0.75\u0026ndash;1.1 mg/kg per dose (mean dose 0.91 mg/kg, mean 13.45 doses, mean total dosage 12.35 mg/kg ); 9\u0026ndash;12 kg, 0.82\u0026ndash;1.2 mg/kg per dose (mean dose 0.96 mg/kg, mean 13 doses, mean total dosage 12.84 mg/kg). Plasma busulfan concentrations were obtained after the first or fifth dose. The fourth or the eighth and subsequent busulfan (Bu/BSF) doses were adjusted to achieve an area under the concentration versus time curve (AUC) of 1125 \u0026micro;mol*min/L\u0026thinsp;\u0026plusmn;\u0026thinsp;10% depending on donor source and disease. After the first dose, median AUC was 758.2 (530.02-1335.9) \u0026micro;mol*min/L. Thirteen infants had Bu IV dose decreased by \u0026gt;\u0026thinsp;10%. Neutrophil and platelet recoveries, grade 2\u0026ndash;4 aGVHD, and nonrelapse mortality (NRM) incidences were 97%, 94%, 11.7%, and 2.9%, respectively. Relapse incidence was 5.9%. Incidence of veno-occlusive disease, hemorrhagic cystitis, and lung toxicities were 9%, 3%, and 6%, respectively. OS and EFS were 91% and 91%.\u003c/p\u003e","manuscriptTitle":"Precision dosing of intravenous busulfan in infants patients undergoing bone marrow transplantation in China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-21 08:27:08","doi":"10.21203/rs.3.rs-5251996/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":"cf7cee3a-a99f-4061-b9bc-53fec15c2a2b","owner":[],"postedDate":"April 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47132797,"name":"Health sciences/Diseases"},{"id":47132798,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-05-09T11:38:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-21 08:27:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5251996","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5251996","identity":"rs-5251996","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}