Drug-drug interaction study between SHC014748M and itraconazole and rifampicin

Drug-drug interaction study between SHC014748M and itraconazole and rifampicin | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Drug-drug interaction study between SHC014748M and itraconazole and rifampicin Jinmei Zhou, Mengshuang Gao, Ning Chen, Yu Peng, Xuemei Lou, Yujie Lv, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7397648/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 Objective To evaluate the pharmacokinetics of SHC014748M under the influence of different drugs . SHC014748M, a selective PI3Kδ inhibitor, has shown potential therapeutic value in patients with CLL/SLL and NHL in clinical studies. Methods This study employed a single-center, two-period, open-label, sequential-dose design. Key pharmacokinetic parameters were calculated using non-compartmental analysis using WinNonlin software (version 8.2). Results Coadministration of SHC014748M with CYP3A4/5 inhibitors or inducers significantly affected the maximum plasma concentration (C max ) , the area under the curve at the cutoff time point (AUC 0-t ), and the area under the curve extending to infinity (AUC 0-∞ ). This drug-drug interaction demonstrated statistically significant differences in pharmacokinetic parameters (90% confidence interval for the geometric mean ratio outside the 80.00% to 125.00% equivalence range). Conclusions Since SHC014748M is a substrate of CYP3A4/5 metabolizers, it may cause drug-drug interactions with CYP3A4/5 inhibitors and inducers during clinical use. In this study, SHC014748M capsules showed good tolerability. Trial registration Registration authority: China Drug Trials, TRN:CTR20201782, Registration date: August 27, 2020. SHC014748M CYP3A4/5 Drug-drug interactions Tolerability Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction SHC014748M 1 is a first-in-class small-molecule PI3Kδ-selective inhibitor independently developed by Nanjing Shenghe Pharmaceutical Co., Ltd. This molecule targets PI3Kδ through a non-ATP competitive mechanism and is designed for the treatment of patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma 2 (iNHL), including subtypes such as follicular lymphoma and marginal zone lymphoma.This highly specific interaction potently inhibits PI3Kδ kinase activity and effectively shuts down its downstream signaling cascade. By interfering with B-cell growth, maturation, and differentiation processes, SHC014748M suppresses the initiation and progression of B-cell malignancies 3 . In nonclinical and early clinical studies, SHC014748M has demonstrated favorable safety and efficacy 4 . In clinical treatment, patients taking multiple medications concurrently may experience drug-drug interactions 5 , also known as drug-drug interactions 6 (DDIs). This can alter the potency or effectiveness of the drugs in the body, potentially leading to more severe adverse reactions or compromising therapeutic efficacy. Preclinical studies have shown that SHC014748M is superior to idelalisib 7 in inhibiting CLL 8 and FL cell proliferation and blocking the pAkt signaling pathway 9 . SHC014748M can completely inhibit the increase in pAkt levels induced by anti-IgM stimulation at a lower concentration (100 nM), demonstrating significant clinical potential and making it suitable for in-depth anti-tumor clinical research 10 . Itraconazole 11 , known as a triazole antifungal, disrupts ergosterol formation in fungal cell membranes and serves as a powerful inhibitor of CYP3A4/5 and P-glycoprotein.Consequently, it can slow the metabolism of drugs that are substrates of CYP3A4/5, leading to increased systemic exposure.Rifampicin 12 , belonging to the rifamycin class of antibiotics, demonstrates significant efficacy against Mycobacterium tuberculosis and is also potent against many Gram-positive and Gram-negative bacteria, as well as some viruses. In clinical DDI studies, rifampicin is commonly employed as a strong CYP3A4/5 inducer 13 . The present investigation is a single-center, open-label drug–drug interaction study designed to evaluate the potential interactions between SHC014748M and itraconazole as well as rifampicin. Additionally, the trial will characterize the pharmacokinetic profile and tolerability of SHC014748M capsules in healthy volunteers, thereby providing critical dosing guidance for subsequent clinical studies 14 . Materials and methods Research material The study drug is SHC014748M capsules,as shown in Fig. 1 , batch number 201911191, with a dosage of 100 mg per capsule and an expiration date of October 2021. They require sealed storage. Itraconazole capsules, marketed as Sporanox®, batch number KBJ15H7, contain 100 mg per capsule and are expiration date of January 2022. They require sealed storage in a dry environment below 25°C. These capsules are manufactured by Xi'an Janssen Pharmaceutical Co. Ltd. Rifampicin capsules, batch number 2004011, contain 300 mg per capsule and are expiration date of March 2022. They require sealed storage in a dark, dry place. They are manufactured by Shenyang Hongqi Pharmaceutical Co., Ltd. All drugs were provided by Nanjing Shenghe Pharmaceutical Co., Ltd. Subject selection In this trial, 40 healthy male subjects were involved, split into 20 in the SHC014748M plus itraconazole group and 20 in the SHC014748M plus rifampicin group. Based on the results of previous safety pharmacology studies of SHC014748M capsules, safety and tolerability studies with single and multiple dose escalation, and studies of the effects of food on SHC014748M, this study enrolled healthy adult males. Nanjing Shenghe Pharmaceutical Co., Ltd. obtained clinical trial approval for SHC014748M capsules (100 mg) in February 2018 (approval numbers: 2018L02123 and 2018L02124) and commissioned the primary affiliated hospital of Bengbu Medical College to conduct the study. This clinical trial was approved by the Ethics Committee of the First Affiliated Hospital of Bengbu Medical College and was conducted in strict accordance with Good Manufacturing Practice (GCP) requirements and the principles of the Declaration of Helsinki. The investigators explained the relevant issues to the participants in detail before the trial, and all participants provided written informed consent. The trial is registered with www.chinadrugtrials.org.cn , number CTR20201782. In the drug interaction study with itraconazole, subject A011 withdrew from the study due to premature ventricular 15 contractions prior to dosing. Ultimately, 19 subjects completed the study. A total of 20 subjects participated in the drug interaction study with rifampicin. This trial did not employ randomization; subjects were assigned enrollment numbers and entered the trial based on the order in which they qualified after screening.As shown in Table 1 . Table 1 Summary of demographic baseline data Itraconazole (N = 19) Rifampicin (N = 20) Age (y) 26.6 ± 6.8 (18–40) 26.7 ± 5.0 (19–38) Height (cm) 171.6 ± 5.0 (164–184) 170.0 ± 5.8 (159–180) Weight (kg) 65.8 ± 5.6 (58–77) 65.6 ± 7.0 (52–79) BMI (kg/m²) 22.4 ± 1.8 (19.5–25.9) 22.7 ± 2.1 (19.4–25.9) Inclusion criteria The study enrolled healthy males aged 18 to 45 years, weighing between 50.0 and 80.0 kilograms, having a BMI ranging from 19.0 to 26.0 kg/m². All participants underwent a comprehensive health examination, including vital signs, electrocardiogram (ECG), blood tests, urine analysis, liver and kidney function, electrolyte levels, and blood glucose levels, all of which were within normal ranges or deemed clinically insignificant by the investigators. Exclusion criteria included: abnormal clinical manifestations, recent surgery affecting drug metabolism, difficulty swallowing or gastrointestinal history, recent use of liver enzyme inhibitors or inducers, positive antibodies for infectious diseases, allergy history, recent drug use or heavy smoking/drinking, recent use of other medications, inability to follow the study diet, or being deemed unsuitable for the trial by the investigator. These criteria were established to ensure the safety and scientific rigor of the study 16 . Administration method and blood sample collection This study enrolled 40 healthy male subjects. On the first day of the study, participants took 200 mg of SHC014748M capsules with 240 ml of warm water on an empty stomach after fasting for at least 8 hours. They were advised not to drink water for 1 hour before and 2 hours after taking the drug, and not to eat or drink for 4 hours after taking the drug to ensure that drug absorption and metabolism were not affected. In the drug-drug interaction study between SHC014748M and itraconazole, a wash-out period of three days (Days 1–3) was observed. From Day 4 to Day 9, itraconazole capsules were administered within 30 minutes after breakfast; on Day 10 the dose was taken under fasting conditions. A fixed 2-hour interval separated the intake of itraconazole and SHC014748M capsules. Subjects were required to abstain from water for 1 hour before and 2 hours after each study drug administration, and to remain fasted for 4 hours following the SHC014748M dose. Pharmacokinetic blood samples were collected at 1 hour pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours post-dose on Days 1 and 10. To evaluate the potential drug–drug interaction between SHC014748M and rifampicin, subjects first underwent a 3-day wash-out period (Days 1–3). From Day 4 onward, participants received rifampicin 600 mg orally once daily. On Day 8, rifampicin was administered under fasted conditions, followed exactly 2 hours later by a single SHC014748M capsule. Water was prohibited 1 hour before and 2 hours after each dose; food intake was restricted for 4 hours following SHC014748M ingestion. Moreover, Pharmacokinetic blood samples were collected at 1 hour pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours post-dose on Days 1 and 8 to characterize the plasma concentration–time profiles of both agents. For each sampling time point, extract roughly 3 ml of venous blood, put it in a K₂EDTA collection tube, and softly shake it 5 to 10 times to ensure immediate anticoagulation.Within 1.5 h of collection, samples were centrifuged at 4°C and 1500 g for 10 min. Two aliquots of 0.6–0.8 mL supernatant plasma were transferred into separate polypropylene tubes (primary and backup). The plasma samples were stored at -80°C until bioanalysis. Determination method Chromatographic conditions : Column: Ultimate XB C18, 2.1 × 50.0 mm, 5 µm, Welch; Column temperature: 35°C; Injection volume: 2.00 µL; Mobile phase: Mobile phase A: 0.1% formic acid in water; Mobile phase B: 0.1% formic acid in acetonitrile.As shown in Table 2 . Table 2 Gradient elution process of mobile phase Time(min) Flow rate(mL/min) Mobile phase A(%) Mobile phase B(%) 0.00 1.00 70.0 30.0 0.01 1.00 70.0 30.0 1.20 1.00 5.0 95.0 1.80 1.00 5.0 95.0 1.90 1.00 70.0 30.0 2.50 1.00 70.0 30.0 Mass spectrometry conditions : ionization mode: ESI positive ion; scanning mode: multiple reaction monitoring (MRM);Electrospray voltage: 5500 V; ion spray temperature: 600°C; Curtain Gas (CUR): 30 psi;CAD (Collision Activated Dissociation): 9; Both Gas 1 and Gas 2 have a pressure of 60 psi.; Data acquisition time: 2.50 min.As shown in Table 3 . Table 3 Optimized mass parameters for SHC014748M and SHC014748M-d3(Internal standard) Analyte Q1 (Da) Q3 (Da) Dwell (msec) DP (V) EP (V) CE (V) CXP (V) Retention time(min) SHC014748M 417.2 282.2 110 40.0 10.0 31.0 15.0 0.83 SHC014748M-d3 422.0 287.0 110 40.0 10.0 32.0 15.0 0.83 Add 25.0 µL of the plasma sample to a 96-well deep-well plate, then introduce 25.0 µL of 500 ng/mL concentration internal standard solution to each sample and vortex for 3 minutes. Precipitate each sample by adding 400 µL of acetonitrile. Vortex for 5 minutes and centrifuge at 1700 g for 15 minutes at 4°C. Transfer 50.0 µL of the supernatant to another 96-well deep-well plate containing 950 µL of methanol and vortex for 5 minutes. Store the processed samples in the autosampler at 4°C until analysis. Kinetic analysis Spectral acquisition and peak integration for the analyte and internal standard were performed with the Analyst® 1.6.3 software (AB Sciex) facilitated the generation of calibration curves by plotting the y-axis as the peak-area ratio (analyte/internal standard) against the x-axis representing the nominal plasma concentration. Linear regression was carried out using a 1/x² weighted least-squares algorithm, yielding the equation y = ax + b. The resulting regression parameters were imported into Watson LIMS 7.5 for automated calculation and verification of sample concentrations. Drug-drug interactions between SHC014748M and itraconazole and rifampicin were evaluated according to the guidelines for drug interaction studies. Clinically significant drug interactions were considered absent when the 90% confidence intervals for the geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ between SHC014748M combined with the interacting agent and SHC014748M by itself were entirely within the 80.00–125.00% range. The pharmacokinetic parameters C max , AUC 0 − t , and AUC 0−∞ were natural logarithm - transformed. A mixed-effects model was used, with subject as the random effect factor and co-administration/monotherapy as the fixed effect, to calculate the 90% confidence interval of the geometric mean ratio (co-administration/monotherapy) of the pharmacokinetic parameters. Result Safety evaluation results of SHC014748M and itraconazole In healthy male volunteers, SHC014748M 200 mg was administered once daily in the fasted state for 10 consecutive days; itraconazole 200 mg was added from Day 4 onward. No adverse events greater than Grade 3 or leading to discontinuation were reported, and the overall tolerability and safety profile remained favorable. Figures 2 and 3 display the mean plasma concentration–time curves for SHC014748M following a single 200 mg capsule, either administered alone or with 200 mg itraconazole. Descriptive pharmacokinetic parameters of SHC014748M following oral administration of 200 mg SHC014748M alone or with itraconazole 200 mg are summarized in Table 4 . Compared with SHC014748M administered as monotherapy, co-administration with itraconazole for 7 days produced no discernible shift in median T max (values remained identical), while C max and systemic exposure (AUC 0–t and AUC 0–∞ ) increased markedly, and apparent oral clearance (CL/F) trended downward 17 . Table 4 Pharmacokinetic parameters of SHC014748M after a single dose of SHC014748M alone and in combination with itraconazole Parameter SHC014748M alone (N = 19) Combination (N = 19) Cmax (µg/mL) 2.62 ± 1.16 3.86 ± 1.77 AUC0-t (µg/mL·h) 43. 6 ± 21.6 91.9 ± 33.5 AUC0-∞ (µg/mL·h) 46.1 ± 22.9 100 ± 34 Tmax (h) 2.0 (1.0, 6.0) 2.0 (1.0, 6.0) t1/2 (h) 15.1 ± 3.1 20.9 ± 4.8 CL/F (L/h) 4.78 ± 1.73 2.10 ± 0.76 MRT (h) 32.7 ± 47.6 38.1 ± 31.1 Alone, SHC014748M alone; Combination, SHC014748M + itraconazole. Data are shown as arithmetic mean ± standard deviation (SD) and Tmax as median (range). Confidence interval analysis of geometric mean ratios was performed for the main PK parameters of SHC014748M (C max , AUC 0 − t , and AUC 0−∞ ). The results showed that compared with SHC014748M capsules alone, the geometric mean ratios of SHC014748M C max , AUC 0 − t , and AUC 0−∞ after 7 consecutive days of itraconazole capsules combined with SHC014748M capsules (combination/single) were 146.3%, 215.2%, and 224.9%, respectively, all exceeding the 80.00%-125.00% no-effect margin 18 .For SHC014748M, the 90% confidence intervals of the geometric mean ratios for Cmax, AUC0-t, and AUC0-∞ after both combined and single administration were (119.89%-177.39%), (184.08%-252.11%), and (193.41%-262.30%), respectively. The above test results indicate that there is a drug-drug interaction between SHC014748M capsules and the mutagenic drug itraconazole capsules.As shown in Table 5 . Table 5 The 90% confidence interval (90%CI) of geometric mean ratios for the C max , AUC 0 − t and AUC 0−∞ of SHC014748M after a single dose of SHC014748M alone and in combination with itraconazole. Parameter Geometric mean GMR% 90% CI lower 90% CI upper Alone(N = 19) Combination(N = 19) C max (µg/mL) 2.40 3.51 146.3 119.89 177.39 AUC 0 − t (µg/mL·h) 40.2 86.5 215.2 184.08 252.11 AUC 0−∞ (µg/mL·h) 44.9 101 224.9 193.41 262.30 Safety evaluation results of SHC014748M and rifampicin capsules Among the 20 participants, a total of 10 cases (18 episodes) of mild to moderate adverse events occurred, with no severe or withdrawal events reported. When used alone, SHC014748M caused 4 cases (elevated bilirubin, decreased neutrophil count, bradycardia); rifampin alone caused 4 cases (elevated bilirubin, elevated urinary leukocyte count, decreased lymphocyte count); and the combination of both drugs caused 4 cases (elevated triglycerides, elevated ALT/AST, elevated CRP, chest discomfort). Overall, the treatment was safe and well-tolerated. Figures 4 and 5 compare the average plasma concentration-time profiles of SHC014748M in healthy male participants after taking a single 200 mg SHC014748M capsule or alongside a 600 mg rifampin capsule. In healthy male subjects, the descriptive statistical results of SHC014748M's pharmacokinetic properties in plasma following the oral intake of 200 mg SHC014748M capsules on an empty stomach or in combination with 600 mg of rifampin capsules are presented in Table 6 . The pharmacokinetic parameter results indicate that, compared to monotherapy with SHC014748M capsules, co-administration with rifampin capsules after 5 days of continuous rifampin therapy resulted in a slight trend toward a shorter time to peak plasma concentration (T max ) for SHC014748M (the median T max under co-administration was 85.71% of that under monotherapy), the peak concentration (C max ) and exposure (AUC 0 − t , AUC 0−∞ ) showed a significant decrease, while the clearance rate (CL/F) showed a significant increase. Table 6 Pharmacokinetic parameters of SHC014748M after a single dose of SHC014748M alone and in combination with rifampicin Parameter SHC014748M alone (N = 20) Combination (N = 20) C max (µg/mL) 3.15 ± 1.12 1.62 ± 0.54 AUC 0 − t (µg/mL·h) 46.5 ± 16.5 10.4 ± 3.8 AUC 0−∞ (µg/mL·h) 53.4 ± 17.7 10.9 ± 3.9 T max (h) 1.8 (0.5, 4.0) 1.5 (0.5, 4.0) t 1/2 (h) 18.8 ± 7.5 13.5 ± 7.7 CL/F (L/h) 4.44 ± 1.88 19.0 ± 5.8 MRT (h) 28.2 ± 13.0 26.8 ± 62.4 Alone, SHC014748M alone; Combination, SHC014748M + rifampicin. Data are shown as arithmetic mean ± standard deviation (SD) and Tmax as median (range). A geometric mean ratio confidence interval analysis was conducted for the primary PK parameters (C max , AUC 0 − t , and AUC 0−∞ ) of SHC014748M. The results showed that compared with taking SHC014748M capsules alone, co-administration of rifampicin capsules with SHC014748M capsules after 5 days of continuous rifampicin administration resulted in the geometric mean ratio values (combination therapy/monotherapy) for C max , AUC 0 − t , and AUC 0−∞ of SHC014748M were 52.24%, 22.84%, and 22.92%, respectively, all exceeding the 80.00% to 125.00% no-effect boundary range; The 90% confidence intervals for the geometric mean ratios of C max , AUC 0 − t , and AUC 0−∞ of SHC014748M after co-administration and monotherapy, calculated using the [1–2α] confidence interval method, were (42.59% to 64.08%), (20.25% to 25.76%), and (20.23% to 25.96%), respectively. The above experimental results indicate that there is a drug-drug interaction between SHC014748M capsules and the mutagenic drug rifampicin capsules.As shown in Table 7 . Table 7 The 90% confidence interval (90%CI) of geometric mean ratios for the C max , AUC 0 − t and AUC 0−∞ of SHC014748M after a single dose of SHC014748M alone and in combination with rifampicin Parameter Geometric mean(N = 20) GMR% 90% CI lower 90% CI upper Alone Combination C max (µg/mL) 2.92 1.52 52.1 42.59 64.08 AUC 0 − t (µg/mL·h) 43.4 9.91 22.8 20.25 25.76 AUC 0−∞ (µg/mL·h) 48.3 11.1 23.0 20.23 25.96 Alone, SHC014748M alone; Combination, SHC014748M + rifampicin. GMR, (geometric mean SHC014748M + rifampicin) / (geometric mean SHC014748M alone). Safety evaluation Table 8 Adverse events related to the combination and monotherapy of SHC014748M with itraconazole Treatment Phase Adverse Events (AEs) n (%, events) Adverse Drug Reactions (ADRs) n (%, events) Serious AEs/ADRs Leading to Discontinuation Grade 2 AEs (n, events) SHC014748M + Itraconazole 11(57.9%, 16) 11(57.9%, 14) 0 0 Hypertriglyceridemia (2, 2) SHC014748M Alone 9(47.4%, 11) 8(42.1%, 9) 0 0 Hypertriglyceridemia (1, 1) Itraconazole Alone 5(26.3%, 5) 5(26.3%, 5) 0 0 0 Coadministration 0 0 0 0 0 Adverse events ( AEs ) reported with SHC014748M alone included hypertriglyceridemia in two patients (10.5%, two events), hyperuricemia in one patient ( 5.3%, one event), increased blood bilirubin in two patients (10.5%, two events), decreased neutrophil count in one patient (5.3%, one event), supraventricular arrhythmia in two patients (10.5%, three events), and sinus bradycardia in two patients (10.5%, two events). AEs reported with continuous itraconazole administration included hypertriglyceridemia in one patient (5.3%, one event), increased blood bilirubin in two patients (10.5%, two events), increased total bile acids in one patient (5.3%, one event), and supraventricular arrhythmia in one patient (5.3%, one event).As shown in Table 8 . Two AEs were grade 2 in severity, occurring during phases 1 and 2: hypertriglyceridemia in two cases (10.5%, two episodes) and hypertriglyceridemia in one case (5.3%, one episode). All other adverse events were grade 1 in severity. No intervention was taken for any of the AEs reported by the subjects 19 . Table 9 Adverse events related to the combination and monotherapy of SHC014748M with rifampicin Treatment Phase Adverse Events (AEs) n (%, events) Adverse Drug Reactions (ADRs) n (%, events) Serious AEs/ADRs Leading to Discontinuation SHC014748M + Rifampicin 10(50.0%, 18) 9(45.0%, 17) 0 0 SHC014748M Alone 4(20.0%, 4) 3(15.0%, 3) 0 0 Rifampicin Alone 4(20.0%, 6) 4(20.0%, 6) 0 0 Coadministration 4(20.0%, 8) 4(20.0%, 8) 0 0 AEs reported with SHC014748M monotherapy included increased blood bilirubin in one patient (5.0%, 1 episode), decreased neutrophil count in two patients (10.0%, 2 episodes), and sinus bradycardia in one patient (5.0%, 1 episode). AEs reported with continuous rifampicin therapy included increased blood bilirubin in three patients (15.0%, 3 episodes), positive urine leukocytes in two patients (10.0%, 2 episodes), and decreased lymphocyte count in one patient (5.0%, 1 episode). AEs reported with combined therapy included hypertriglyceridemia in one patient (5.0%, 1 episode), increased alanine aminotransferase in three patients (15.0%, 3 episodes), increased aspartate aminotransferase in two patients (10.0%, 2 episodes), increased C-reactive protein in one patient (5.0%, 1 episode), and chest discomfort in one patient (5.0%, 1 episode).As shown in Table 9 . Discussion SHC014748M is a highly selective PI3Kδ inhibitor. Similar drugs include the marketed Idelalisib, Duvelisib, and Copanlisib, as well as clinically tested drugs such as Zandelisib and Linperlisib 20 . Compared to these drugs, SHC014748M's greatest advantage lies in its higher selectivity (306-fold greater than PI3Kα for PI3Kδ and 69-fold greater than idelalisib), stronger in vitro activity, and improved efficacy in inducing tumor cell apoptosis. In early clinical trials, it has demonstrated no severe toxicity or adverse reactions with black box warnings, indicating better overall tolerability. In a drug interaction study between SHC014748M and itraconazole, co-administration of itraconazole (200 mg for 7 consecutive days) with SHC014748M did not significantly alter the peak time (T max ) of SHC014748M ( median values were consistent with monotherapy). However, peak concentration (C max ) and exposure (AUC 0 − t and AUC 0−∞ ) significantly increased, while clearance (CL/F) decreased. Furthermore, in a drug interaction study between SHC014748M and rifampicin, co-administration of rifampicin (600 mg for 5 consecutive days) with SHC014748M slightly shortened the peak time (T max ) of SHC014748M ( median value was 85.7% of monotherapy), significantly decreased peak concentration (C max ) and exposure (AUC 0 − t and AUC 0−∞ ), and significantly increased clearance (CL/F). Compared with SHC014748M alone, after 7 consecutive days of itraconazole administration 21 , the geometric mean ratios of SHC014748M C max , AUC 0 − t , and AUC 0−∞ (combination/single) were 145.3%, 215.2%, and 224.9%, respectively. Compared with SHC014748M alone, after 5 consecutive days of rifampicin administration, the geometric mean ratios of SHC014748M C max , AUC 0 − t , and AUC 0−∞ (combination/single) were 52.1%, 22.8%, and 23.0%, respectively. These values are outside the 80.00%–125.00% effect range. Therefore, significant drug-drug interactions exist between SHC014748M and the mutagenic agents itraconazole and rifampicin 22 .The cytochrome P450 3A4/5 enzyme (CYP3A4/5) inhibitor itraconazole has a moderate inhibitory effect 23 on the metabolic elimination of SHC014748M23, and the cytochrome P450 3A4/5 enzyme (CYP3A4/5) inducer 24 rifampicin has a moderate induction effect on the metabolic elimination of SHC014748M24 .Co-administration of itraconazole with SHC014748M for 7 consecutive days increased the human exposure to SHC014748M by approximately 2.2 times that of SHC014748M alone, an increase in exposure that may be clinically significant. Conversely, co-administration of rifampicin with SHC014748M for 5 consecutive days reduced the human exposure to approximately 23% of SHC014748M alone, a significant decrease in exposure that may also be clinically significant. In this study, SHC014748M capsules were generally well tolerated. Compared with either SHC014748M capsules or itraconazole capsules alone, combined use of the two drugs increased only the incidence of elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST), there was no significant rise in the overall occurrence of other adverse reactions or in the occurrence of specific adverse reactions. Furthermore, compared with either SHC014748M capsules or rifampicin capsules alone, the combined use of the two drugs did not increase the overall incidence of adverse reactions or the incidence of individual adverse reactions 25 . In summary, this study aimed to investigate significant drug-drug interactions between SHC014748M and both itraconazole and rifampicin. Itraconazole significantly increased SHC014748M exposure, while rifampicin significantly decreased SHC014748M exposure. These interactions may have important clinical implications, necessitating careful evaluation and dose adjustment when coadministered. Furthermore, SHC014748M capsules were well tolerated in this study, with no new safety concerns identified. Abbreviations PI3Kδ Phosphoinositide 3-kinase delta CLL Chronic lymphocytic leukemia SLL Small lymphocytic lymphoma NHL Non-Hodgkin lymphoma iNHL indolent B-cell non-Hodgkin lymphoma CYP3A4/5 Cytochrome P450 3A4/5 DDI drug–drug interaction AUC₀-t Area under the concentration-time curve from zero up to a definite time t AUC₀-∞ Curve from zero up to ∞ with extrapolation of the terminal phase CL/F Apparent total plasma or serum clearance of drug after oral administration GCP Good Clinical Practice AE Adverse Event Declarations Ethics approval and consent to participate This clinical trial was approved by the Clinical Medical Research Ethics Committee of the First Affiliated Hospital of Bengbu Medical College. The study was conducted in strict accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) standards. Before any study-related procedures, the investigator explained to each prospective participant the nature, objectives, procedures, expected duration, potential risks, anticipated benefits, and possible discomforts of the trial, and written informed consent was obtained from all participants. The trial was registered with the China Drug Trials Registry (www.chinadrugtrials.org.cn, registration number CTR20201782, registration date: 27 August 2020). Consent for publication Not applicable. Availability of data and materials All data generated or analyzed during this study are included in this published article and its supplementary information files. Competing Interests All authors declare no conflict of interest. Funding Major Natural Science Research Projects of Universities in Anhui Province (No.2023AH040406; No.2023AH040290). Authors' contributions JM.Z. conceived and designed the study, performed the experiments, analyzed the data, and wrote the original draft.MS.G curated the data and performed formal analysis.All authors read and approved the final manuscript.Besides all authors declare no competing interests. Acknowledgements This work was financially supported by Major Natural Science Research Projects of Universities in Anhui Province (No.2023AH040406; No.2023AH040290). References Fan L, Wang C, Zhao L, et al. SHC014748M, a novel selective inhi-bitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B cell lymphomas and chronic lymphocytic leukemia. Neoplasia. Dec 2020;22(12):714-724. Zhuang TZ, Zhang C, Strati P. SOHO State of the Art Updates and Next Questions | Novel Immunotherapy Combinations for the Treatment of Indolent B-Cell Lymphoma. Clin Lymphoma Myeloma Leuk. Jul 2025;25(7):455-464. Willard P, McKay J, Yazbeck V. Role of antibody-based therapy in indolent non-Hodgkin's lymphoma. Leuk Res Rep. 2021;16:100275. Guo F, Liu B, Li X, et al. Mass balance, metabolic disposition, and pharmacokinetics of a novel selective inhibitor of PI3Kδ [(14)C] SHC014748M in healthy Chinese subjects following oral administration. Cancer Chemother Pharmacol. Feb 2023;91(2):143-156. Pafili K, Papanas N. Considerations for single- versus multiple-drug pharmacotherapy in the management of painful diabetic neuropathy. Expert Opin Pharmacother. Nov 2021;22(16):2267-2280. Zhu V, Burhenne J, Weiss J, et al. Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers. Front Pharmacol. 2023;14:1128547. Zhu J, Jia L, Jiang Y, et al. Integrated molecular modeling techniques to reveal selective mechanisms of inhibitors to PI3Kδ with marketed Idelalisib. Chem Biol Drug Des. Jun 2021;97(6):1158-1169. Zoulikha M, He W. Targeted Drug Delivery for Chronic Lymphocytic Leukemia. Pharm Res. Mar 2022;39(3):441-461. Zuo T, Liu Y, Duan M, et al. Platelet-derived growth factor PDGF-AA upregulates connexin 43 expression and promotes gap junction formations in osteoblast cells through p-Akt signaling. Biochem Biophys Rep. Jul 2023;34:101462. Zinzani PL, Wang H, Feng J, et al. CHRONOS-4: phase 3 study of copanlisib plus rituximab-based immunochemotherapy in relapsed indolent B-cell lymphoma. Blood Adv. Sep 24 2024;8(18):4866-4876. Zhou M, Hu C, Yin Y, et al. Experimental Evolution of Multidrug Resistance in Neurospora crassa under Antifungal Azole Stress. J Fungi (Basel). Feb 18 2022;8(2). Zuo D, Lv L, Ren H, Sun H. Effects of polyphenols extracted from Keemun black tea on CYP450s activity and molecular mechanisms. Food Sci Nutr. Oct 2024;12(10):7306-7315. Wang K, Ding J, Li X, et al. Effects of itraconazole and rifampicin on the pharmacokinetics and safety of youkenafil, a novel phosphodiesterase type 5 inhibitor, in healthy Chinese subjects. Eur J Pharm Sci. Aug 1 2022;175:106213. Zou Y, Xu W, Li J. Chimeric antigen receptor-modified T cell therapy in chronic lymphocytic leukemia. J Hematol Oncol. Nov 20 2018;11(1):130. Li H, Yang Y, Wang P, et al. [Clinical and genetic analysis of a case of Triadin knockout syndrome due to variant of TRDN gene and a literature review]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. Nov 10 2024;41(11):1323-1329. Pan L, Xiao X, Liu S, Peng S. An Integration Framework of Secure Multiparty Computation and Deep Neural Network for Improving Drug-Drug Interaction Predictions. J Comput Biol. Sep 2023;30(9):1034-1045. Zyryanov S, Bondareva I, Butranova O, Kazanova A. Population PK/PD modelling of meropenem in preterm newborns based on therapeutic drug monitoring data. Front Pharmacol. 2023;14:1079680. Zwittnig K, Kirnbauer B, Truschnegg A, et al. Effectiveness of platelet-rich fibrin in third molar extractions: a randomized controlled split-mouth study. Clin Oral Investig. Oct 29 2024;28(11):615. Zhou T, Xu W, Zhang W, et al. Preclinical profile and phase I clinical trial of a novel androgen receptor antagonist GT0918 in castration-resistant prostate cancer. Eur J Cancer. Jul 2020;134:29-40. Witkowska M, Majchrzak A, Robak P, Wolska-Washer A, Robak T. Metabolic and toxicological considerations for phosphoinositide 3-kinase delta inhibitors in the treatment of chronic lymphocytic leukemia. Expert Opin Drug Metab Toxicol. Sep 2023;19(9):617-633. Kucukkaya IC, Gulsever CI, Dolas I, et al. First case of Rhinocladiella mackenziei brain abscess in Turkey: Case report and review of the literature. Mycoses. Sep 2023;66(9):755-766. Mukonzo JK, Kengo A, Kutesa B, et al. Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB-rifampicin sensitivity among Ugandan patients. Trans R Soc Trop Med Hyg. Feb 7 2020;114(2):107-114. Zubiaur P, Benedicto MD, Villapalos-García G, et al. SLCO1B1 Phenotype and CYP3A5 Polymorphism Significantly Affect Atorvastatin Bioavailability. J Pers Med. Mar 13 2021;11(3). Zhang Y, Wang Z, Wang Y, et al. CYP3A4 and CYP3A5: the crucial roles in clinical drug metabolism and the significant implications of genetic polymorphisms. PeerJ. 2024;12:e18636. Żychowska M, Żychowska M. No evidence for association between cutaneous lichen planus and hepatitis B and C virus infection in south Poland - a case-control study. Int J Dermatol. Jun 2020;59(6):698-703. 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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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7397648","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":531760236,"identity":"2e27c308-4c07-4e86-81f5-fee054132450","order_by":0,"name":"Jinmei Zhou","email":"","orcid":"","institution":"Clinical Trial Center of the First Affiliated Hospital of Bengbu Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jinmei","middleName":"","lastName":"Zhou","suffix":""},{"id":531760237,"identity":"1c7ff33b-3640-4c0b-b72f-be9103317b34","order_by":1,"name":"Mengshuang Gao","email":"","orcid":"","institution":"Bengbu 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1","display":"","copyAsset":false,"role":"figure","size":18443,"visible":true,"origin":"","legend":"\u003cp\u003eStructural formular for SHC014748M\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7397648/v1/08d320a4642ff39c0747f448.png"},{"id":94138562,"identity":"e74c77f0-4938-4677-a6da-fc65bc8d06fc","added_by":"auto","created_at":"2025-10-22 19:29:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":77434,"visible":true,"origin":"","legend":"\u003cp\u003ePlasma concentration-time profiles (mean + SD) of SHC014748M after a single dose, both alone (n = 19) and with itraconazole (n = 19).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7397648/v1/3e342c8cd5ebec1181f827ec.png"},{"id":94139947,"identity":"3c6bd8d7-17a5-440f-b59f-6aa3f863b232","added_by":"auto","created_at":"2025-10-22 19:37:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":76388,"visible":true,"origin":"","legend":"\u003cp\u003eMean plasma concentration-time semi-log profiles (mean + SD) of SHC014748M after a single dose of SHC014748M alone (n = 19) and in combination with itraconazole (n = 19)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7397648/v1/bcb39b16522202118bc721e0.png"},{"id":94138563,"identity":"311850eb-7828-432d-ad79-32940e06de61","added_by":"auto","created_at":"2025-10-22 19:29:40","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":69562,"visible":true,"origin":"","legend":"\u003cp\u003eMean plasma concentration-time profiles (mean + SD) of SHC014748M after a single dose of SHC014748M alone (n = 20) and in combination with rifampicin (n = 20)\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7397648/v1/70f9eb8d0a5fe544dc5c8415.png"},{"id":94137027,"identity":"586c0d73-3f12-490b-aa84-ffa2628924b7","added_by":"auto","created_at":"2025-10-22 19:21:40","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":79792,"visible":true,"origin":"","legend":"\u003cp\u003eMean plasma concentration-time semi-log profiles (mean + SD) of SHC014748M after a single dose of SHC014748M alone (n = 20) and in combination with rifampicin (n = 20)\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7397648/v1/3bca3de96e7a6c98fcaf0cde.png"},{"id":104428769,"identity":"be9a7744-ed83-49c7-b600-d5475701421e","added_by":"auto","created_at":"2026-03-11 15:12:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1345418,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7397648/v1/912ce87a-36e8-4c3a-924f-5c4584354ba8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Drug-drug interaction study between SHC014748M and itraconazole and rifampicin","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSHC014748M\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e is a first-in-class small-molecule PI3Kδ-selective inhibitor independently developed by Nanjing Shenghe Pharmaceutical Co., Ltd. This molecule targets PI3Kδ through a non-ATP competitive mechanism and is designed for the treatment of patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e (iNHL), including subtypes such as follicular lymphoma and marginal zone lymphoma.This highly specific interaction potently inhibits PI3Kδ kinase activity and effectively shuts down its downstream signaling cascade. By interfering with B-cell growth, maturation, and differentiation processes, SHC014748M suppresses the initiation and progression of B-cell malignancies\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn nonclinical and early clinical studies, SHC014748M has demonstrated favorable safety and efficacy\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. In clinical treatment, patients taking multiple medications concurrently may experience drug-drug interactions\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, also known as drug-drug interactions\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e (DDIs). This can alter the potency or effectiveness of the drugs in the body, potentially leading to more severe adverse reactions or compromising therapeutic efficacy. Preclinical studies have shown that SHC014748M is superior to idelalisib \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003ein inhibiting CLL\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e and FL cell proliferation and blocking the pAkt signaling pathway\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. SHC014748M can completely inhibit the increase in pAkt levels induced by anti-IgM stimulation at a lower concentration (100 nM), demonstrating significant clinical potential and making it suitable for in-depth anti-tumor clinical research \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eItraconazole\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, known as a triazole antifungal, disrupts ergosterol formation in fungal cell membranes and serves as a powerful inhibitor of CYP3A4/5 and P-glycoprotein.Consequently, it can slow the metabolism of drugs that are substrates of CYP3A4/5, leading to increased systemic exposure.Rifampicin\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, belonging to the rifamycin class of antibiotics, demonstrates significant efficacy against Mycobacterium tuberculosis and is also potent against many Gram-positive and Gram-negative bacteria, as well as some viruses. In clinical DDI studies, rifampicin is commonly employed as a strong CYP3A4/5 inducer\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe present investigation is a single-center, open-label drug\u0026ndash;drug interaction study designed to evaluate the potential interactions between SHC014748M and itraconazole as well as rifampicin. Additionally, the trial will characterize the pharmacokinetic profile and tolerability of SHC014748M capsules in healthy volunteers, thereby providing critical dosing guidance for subsequent clinical studies\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eResearch material\u003c/h2\u003e\n \u003cp\u003eThe study drug is SHC014748M capsules,as shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, batch number 201911191, with a dosage of 100 mg per capsule and an expiration date of October 2021. They require sealed storage. Itraconazole capsules, marketed as Sporanox\u0026reg;, batch number KBJ15H7, contain 100 mg per capsule and are expiration date of January 2022. They require sealed storage in a dry environment below 25\u0026deg;C. These capsules are manufactured by Xi\u0026apos;an Janssen Pharmaceutical Co. Ltd. Rifampicin capsules, batch number 2004011, contain 300 mg per capsule and are expiration date of March 2022. They require sealed storage in a dark, dry place. They are manufactured by Shenyang Hongqi Pharmaceutical Co., Ltd. All drugs were provided by Nanjing Shenghe Pharmaceutical Co., Ltd.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSubject selection\u003c/h3\u003e\n\u003cp\u003eIn this trial, 40 healthy male subjects were involved, split into 20 in the SHC014748M plus itraconazole group and 20 in the SHC014748M plus rifampicin group.\u003c/p\u003e\n\u003cp\u003eBased on the results of previous safety pharmacology studies of SHC014748M capsules, safety and tolerability studies with single and multiple dose escalation, and studies of the effects of food on SHC014748M, this study enrolled healthy adult males. Nanjing Shenghe Pharmaceutical Co., Ltd. obtained clinical trial approval for SHC014748M capsules (100 mg) in February 2018 (approval numbers: 2018L02123 and 2018L02124) and commissioned the primary affiliated hospital of Bengbu Medical College to conduct the study. This clinical trial was approved by the Ethics Committee of the First Affiliated Hospital of Bengbu Medical College and was conducted in strict accordance with Good Manufacturing Practice (GCP) requirements and the principles of the Declaration of Helsinki. The investigators explained the relevant issues to the participants in detail before the trial, and all participants provided written informed consent. The trial is registered with \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.chinadrugtrials.org.cn\u003c/span\u003e\u003c/span\u003e, number CTR20201782.\u003c/p\u003e\n\u003cp\u003eIn the drug interaction study with itraconazole, subject A011 withdrew from the study due to premature ventricular\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e contractions prior to dosing. Ultimately, 19 subjects completed the study. A total of 20 subjects participated in the drug interaction study with rifampicin. This trial did not employ randomization; subjects were assigned enrollment numbers and entered the trial based on the order in which they qualified after screening.As shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSummary of demographic baseline data\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eItraconazole (N\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRifampicin (N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8 (18\u0026ndash;40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0 (19\u0026ndash;38)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHeight (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e171.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0 (164\u0026ndash;184)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e170.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8 (159\u0026ndash;180)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeight (kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e65.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.6 (58\u0026ndash;77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e65.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.0 (52\u0026ndash;79)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI (kg/m\u0026sup2;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8 (19.5\u0026ndash;25.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 (19.4\u0026ndash;25.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eInclusion criteria\u003c/h3\u003e\n\u003cp\u003eThe study enrolled healthy males aged 18 to 45 years, weighing between 50.0 and 80.0 kilograms, having a BMI ranging from 19.0 to 26.0 kg/m\u0026sup2;. All participants underwent a comprehensive health examination, including vital signs, electrocardiogram (ECG), blood tests, urine analysis, liver and kidney function, electrolyte levels, and blood glucose levels, all of which were within normal ranges or deemed clinically insignificant by the investigators. Exclusion criteria included: abnormal clinical manifestations, recent surgery affecting drug metabolism, difficulty swallowing or gastrointestinal history, recent use of liver enzyme inhibitors or inducers, positive antibodies for infectious diseases, allergy history, recent drug use or heavy smoking/drinking, recent use of other medications, inability to follow the study diet, or being deemed unsuitable for the trial by the investigator. These criteria were established to ensure the safety and scientific rigor of the study\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eAdministration method and blood sample collection\u003c/h3\u003e\n\u003cp\u003eThis study enrolled 40 healthy male subjects. On the first day of the study, participants took 200 mg of SHC014748M capsules with 240 ml of warm water on an empty stomach after fasting for at least 8 hours. They were advised not to drink water for 1 hour before and 2 hours after taking the drug, and not to eat or drink for 4 hours after taking the drug to ensure that drug absorption and metabolism were not affected.\u003c/p\u003e\n\u003cp\u003eIn the drug-drug interaction study between SHC014748M and itraconazole, a wash-out period of three days (Days 1\u0026ndash;3) was observed. From Day 4 to Day 9, itraconazole capsules were administered within 30 minutes after breakfast; on Day 10 the dose was taken under fasting conditions. A fixed 2-hour interval separated the intake of itraconazole and SHC014748M capsules. Subjects were required to abstain from water for 1 hour before and 2 hours after each study drug administration, and to remain fasted for 4 hours following the SHC014748M dose. Pharmacokinetic blood samples were collected at 1 hour pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours post-dose on Days 1 and 10.\u003c/p\u003e\n\u003cp\u003eTo evaluate the potential drug\u0026ndash;drug interaction between SHC014748M and rifampicin, subjects first underwent a 3-day wash-out period (Days 1\u0026ndash;3). From Day 4 onward, participants received rifampicin 600 mg orally once daily. On Day 8, rifampicin was administered under fasted conditions, followed exactly 2 hours later by a single SHC014748M capsule. Water was prohibited 1 hour before and 2 hours after each dose; food intake was restricted for 4 hours following SHC014748M ingestion. Moreover, Pharmacokinetic blood samples were collected at 1 hour pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours post-dose on Days 1 and 8 to characterize the plasma concentration\u0026ndash;time profiles of both agents.\u003c/p\u003e\n\u003cp\u003eFor each sampling time point, extract roughly 3 ml of venous blood, put it in a K₂EDTA collection tube, and softly shake it 5 to 10 times to ensure immediate anticoagulation.Within 1.5 h of collection, samples were centrifuged at 4\u0026deg;C and 1500 g for 10 min. Two aliquots of 0.6\u0026ndash;0.8 mL supernatant plasma were transferred into separate polypropylene tubes (primary and backup). The plasma samples were stored at -80\u0026deg;C until bioanalysis.\u003c/p\u003e\n\u003ch3\u003eDetermination method\u003c/h3\u003e\n\u003cp\u003eChromatographic conditions : Column: Ultimate XB C18, 2.1 \u0026times; 50.0 mm, 5 \u0026micro;m, Welch; Column temperature: 35\u0026deg;C; Injection volume: 2.00 \u0026micro;L; Mobile phase: Mobile phase A: 0.1% formic acid in water; Mobile phase B: 0.1% formic acid in acetonitrile.As shown in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eGradient elution process of mobile phase\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eTime(min)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFlow rate(mL/min)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMobile phase A(%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMobile phase B(%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eMass spectrometry conditions : ionization mode: ESI positive ion; scanning mode: multiple reaction monitoring (MRM);Electrospray voltage: 5500 V; ion spray temperature: 600\u0026deg;C; Curtain Gas (CUR): 30 psi;CAD (Collision Activated Dissociation): 9; Both Gas 1 and Gas 2 have a pressure of 60 psi.; Data acquisition time: 2.50 min.As shown in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eOptimized mass parameters for SHC014748M and SHC014748M-d3(Internal standard)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAnalyte\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003cp\u003e(Da)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eQ3\u003c/p\u003e\n \u003cp\u003e(Da)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDwell\u003c/p\u003e\n \u003cp\u003e(msec)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDP\u003c/p\u003e\n \u003cp\u003e(V)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEP\u003c/p\u003e\n \u003cp\u003e(V)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCE\u003c/p\u003e\n \u003cp\u003e(V)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCXP\u003c/p\u003e\n \u003cp\u003e(V)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRetention time(min)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSHC014748M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e417.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e282.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSHC014748M-d3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e422.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e287.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAdd 25.0 \u0026micro;L of the plasma sample to a 96-well deep-well plate, then introduce 25.0 \u0026micro;L of 500 ng/mL concentration internal standard solution to each sample and vortex for 3 minutes. Precipitate each sample by adding 400 \u0026micro;L of acetonitrile. Vortex for 5 minutes and centrifuge at 1700 g for 15 minutes at 4\u0026deg;C. Transfer 50.0 \u0026micro;L of the supernatant to another 96-well deep-well plate containing 950 \u0026micro;L of methanol and vortex for 5 minutes. Store the processed samples in the autosampler at 4\u0026deg;C until analysis.\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eKinetic analysis\u003c/h2\u003e\n \u003cp\u003eSpectral acquisition and peak integration for the analyte and internal standard were performed with the Analyst\u0026reg; 1.6.3 software (AB Sciex) facilitated the generation of calibration curves by plotting the y-axis as the peak-area ratio (analyte/internal standard) against the x-axis representing the nominal plasma concentration. Linear regression was carried out using a 1/x\u0026sup2; weighted least-squares algorithm, yielding the equation y\u0026thinsp;=\u0026thinsp;ax\u0026thinsp;+\u0026thinsp;b. The resulting regression parameters were imported into Watson LIMS 7.5 for automated calculation and verification of sample concentrations.\u003c/p\u003e\n \u003cp\u003eDrug-drug interactions between SHC014748M and itraconazole and rifampicin were evaluated according to the guidelines for drug interaction studies. Clinically significant drug interactions were considered absent when the 90% confidence intervals for the geometric mean ratios of Cmax, AUC0-t, and AUC0-\u0026infin; between SHC014748M combined with the interacting agent and SHC014748M by itself were entirely within the 80.00\u0026ndash;125.00% range.\u003c/p\u003e\n \u003cp\u003eThe pharmacokinetic parameters C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e were natural logarithm - transformed. A mixed-effects model was used, with subject as the random effect factor and co-administration/monotherapy as the fixed effect, to calculate the 90% confidence interval of the geometric mean ratio (co-administration/monotherapy) of the pharmacokinetic parameters.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eSafety evaluation results of SHC014748M and itraconazole\u003c/h2\u003e\u003cp\u003eIn healthy male volunteers, SHC014748M 200 mg was administered once daily in the fasted state for 10 consecutive days; itraconazole 200 mg was added from Day 4 onward. No adverse events greater than Grade 3 or leading to discontinuation were reported, and the overall tolerability and safety profile remained favorable.\u003c/p\u003e\u003cp\u003eFigures \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e display the mean plasma concentration\u0026ndash;time curves for SHC014748M following a single 200 mg capsule, either administered alone or with 200 mg itraconazole.\u003c/p\u003e\u003cp\u003eDescriptive pharmacokinetic parameters of SHC014748M following oral administration of 200 mg SHC014748M alone or with itraconazole 200 mg are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eCompared with SHC014748M administered as monotherapy, co-administration with itraconazole for 7 days produced no discernible shift in median T\u003csub\u003emax\u003c/sub\u003e (values remained identical), while C\u003csub\u003emax\u003c/sub\u003e and systemic exposure (AUC\u003csub\u003e0\u0026ndash;t\u003c/sub\u003e and AUC\u003csub\u003e0\u0026ndash;\u0026infin;\u003c/sub\u003e) increased markedly, and apparent oral clearance (CL/F) trended downward\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\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\u003ePharmacokinetic parameters of SHC014748M after a single dose of SHC014748M alone and in combination with itraconazole\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\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\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\u003eSHC014748M alone (N\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCombination (N\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCmax (\u0026micro;g/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.62\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.86\u0026thinsp;\u0026plusmn;\u0026thinsp;1.77\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAUC0-t (\u0026micro;g/mL\u0026middot;h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43. 6\u0026thinsp;\u0026plusmn;\u0026thinsp;21.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e91.9\u0026thinsp;\u0026plusmn;\u0026thinsp;33.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAUC0-\u0026infin; (\u0026micro;g/mL\u0026middot;h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46.1\u0026thinsp;\u0026plusmn;\u0026thinsp;22.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100\u0026thinsp;\u0026plusmn;\u0026thinsp;34\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTmax (h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.0 (1.0, 6.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.0 (1.0, 6.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003et1/2 (h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCL/F (L/h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.78\u0026thinsp;\u0026plusmn;\u0026thinsp;1.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMRT (h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32.7\u0026thinsp;\u0026plusmn;\u0026thinsp;47.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38.1\u0026thinsp;\u0026plusmn;\u0026thinsp;31.1\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\u003eAlone, SHC014748M alone; Combination, SHC014748M\u0026thinsp;+\u0026thinsp;itraconazole.\u003c/p\u003e\u003cp\u003eData are shown as arithmetic mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) and Tmax as median (range).\u003c/p\u003e\u003cp\u003eConfidence interval analysis of geometric mean ratios was performed for the main PK parameters of SHC014748M (C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e). The results showed that compared with SHC014748M capsules alone, the geometric mean ratios of SHC014748M C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e after 7 consecutive days of itraconazole capsules combined with SHC014748M capsules (combination/single) were 146.3%, 215.2%, and 224.9%, respectively, all exceeding the 80.00%-125.00% no-effect margin\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.For SHC014748M, the 90% confidence intervals of the geometric mean ratios for Cmax, AUC0-t, and AUC0-\u0026infin; after both combined and single administration were (119.89%-177.39%), (184.08%-252.11%), and (193.41%-262.30%), respectively.\u003c/p\u003e\u003cp\u003eThe above test results indicate that there is a drug-drug interaction between SHC014748M capsules and the mutagenic drug itraconazole capsules.As shown in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe 90% confidence interval (90%CI) of geometric mean ratios for the C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e of SHC014748M after a single dose of SHC014748M alone and in combination with itraconazole.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eGeometric mean\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eGMR%\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e90% CI lower\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e90% CI upper\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAlone(N\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCombination(N\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eC\u003c/em\u003e\u003csub\u003emax\u003c/sub\u003e (\u0026micro;g/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e146.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e119.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e177.39\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eAUC\u003c/em\u003e\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e (\u0026micro;g/mL\u0026middot;h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e86.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e215.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e184.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e252.11\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eAUC\u003c/em\u003e\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e (\u0026micro;g/mL\u0026middot;h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e224.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e193.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e262.30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSafety evaluation results of SHC014748M and rifampicin capsules\u003c/h2\u003e\u003cp\u003eAmong the 20 participants, a total of 10 cases (18 episodes) of mild to moderate adverse events occurred, with no severe or withdrawal events reported. When used alone, SHC014748M caused 4 cases (elevated bilirubin, decreased neutrophil count, bradycardia); rifampin alone caused 4 cases (elevated bilirubin, elevated urinary leukocyte count, decreased lymphocyte count); and the combination of both drugs caused 4 cases (elevated triglycerides, elevated ALT/AST, elevated CRP, chest discomfort). Overall, the treatment was safe and well-tolerated.\u003c/p\u003e\u003cp\u003eFigures \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e compare the average plasma concentration-time profiles of SHC014748M in healthy male participants after taking a single 200 mg SHC014748M capsule or alongside a 600 mg rifampin capsule.\u003c/p\u003e\u003cp\u003eIn healthy male subjects, the descriptive statistical results of SHC014748M's pharmacokinetic properties in plasma following the oral intake of 200 mg SHC014748M capsules on an empty stomach or in combination with 600 mg of rifampin capsules are presented in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eThe pharmacokinetic parameter results indicate that, compared to monotherapy with SHC014748M capsules, co-administration with rifampin capsules after 5 days of continuous rifampin therapy resulted in a slight trend toward a shorter time to peak plasma concentration (T\u003csub\u003emax\u003c/sub\u003e) for SHC014748M (the median T\u003csub\u003emax\u003c/sub\u003e under co-administration was 85.71% of that under monotherapy), the peak concentration (C\u003csub\u003emax\u003c/sub\u003e) and exposure (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e) showed a significant decrease, while the clearance rate (CL/F) showed a significant increase.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePharmacokinetic parameters of SHC014748M after a single dose of SHC014748M alone and in combination with rifampicin\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\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\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\u003eSHC014748M alone (N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCombination (N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eC\u003c/em\u003e\u003csub\u003emax\u003c/sub\u003e (\u0026micro;g/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.15\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eAUC\u003c/em\u003e\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e (\u0026micro;g/mL\u0026middot;h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46.5\u0026thinsp;\u0026plusmn;\u0026thinsp;16.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eAUC\u003c/em\u003e\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e (\u0026micro;g/mL\u0026middot;h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53.4\u0026thinsp;\u0026plusmn;\u0026thinsp;17.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eT\u003c/em\u003e\u003csub\u003emax\u003c/sub\u003e (h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.8 (0.5, 4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.5 (0.5, 4.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003et\u003c/em\u003e\u003csub\u003e1/2\u003c/sub\u003e (h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eCL/F\u003c/em\u003e (L/h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.44\u0026thinsp;\u0026plusmn;\u0026thinsp;1.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eMRT\u003c/em\u003e (h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26.8\u0026thinsp;\u0026plusmn;\u0026thinsp;62.4\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\u003eAlone, SHC014748M alone; Combination, SHC014748M\u0026thinsp;+\u0026thinsp;rifampicin.\u003c/p\u003e\u003cp\u003eData are shown as arithmetic mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) and Tmax as median (range).\u003c/p\u003e\u003cp\u003eA geometric mean ratio confidence interval analysis was conducted for the primary PK parameters (C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e) of SHC014748M. The results showed that compared with taking SHC014748M capsules alone, co-administration of rifampicin capsules with SHC014748M capsules after 5 days of continuous rifampicin administration resulted in the geometric mean ratio values (combination therapy/monotherapy) for C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e of SHC014748M were 52.24%, 22.84%, and 22.92%, respectively, all exceeding the 80.00% to 125.00% no-effect boundary range; The 90% confidence intervals for the geometric mean ratios of C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e of SHC014748M after co-administration and monotherapy, calculated using the [1\u0026ndash;2α] confidence interval method, were (42.59% to 64.08%), (20.25% to 25.76%), and (20.23% to 25.96%), respectively.\u003c/p\u003e\u003cp\u003eThe above experimental results indicate that there is a drug-drug interaction between SHC014748M capsules and the mutagenic drug rifampicin capsules.As shown in Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe 90% confidence interval (90%CI) of geometric mean ratios for the C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e of SHC014748M after a single dose of SHC014748M alone and in combination with rifampicin\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eGeometric mean(N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eGMR%\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e90% CI lower\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e90% CI upper\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAlone\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCombination\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eC\u003c/em\u003e\u003csub\u003emax\u003c/sub\u003e (\u0026micro;g/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e52.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e42.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e64.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eAUC\u003c/em\u003e\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e (\u0026micro;g/mL\u0026middot;h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e25.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eAUC\u003c/em\u003e\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e (\u0026micro;g/mL\u0026middot;h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e48.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e23.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e25.96\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\u003eAlone, SHC014748M alone; Combination, SHC014748M\u0026thinsp;+\u0026thinsp;rifampicin.\u003c/p\u003e\u003cp\u003eGMR, (geometric mean SHC014748M\u0026thinsp;+\u0026thinsp;rifampicin) / (geometric mean SHC014748M alone).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eSafety evaluation\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab8\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 8\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAdverse events related to the combination and monotherapy of SHC014748M with itraconazole\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment Phase\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAdverse Events (AEs)\u003c/p\u003e\u003cp\u003en (%, events)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAdverse Drug Reactions (ADRs)\u003c/p\u003e\u003cp\u003en (%, events)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSerious AEs/ADRs\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLeading to Discontinuation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGrade 2 AEs (n, events)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSHC014748M\u0026thinsp;+\u0026thinsp;Itraconazole\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11(57.9%, 16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11(57.9%, 14)\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHypertriglyceridemia (2, 2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSHC014748M Alone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9(47.4%, 11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8(42.1%, 9)\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHypertriglyceridemia (1, 1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eItraconazole Alone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5(26.3%, 5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5(26.3%, 5)\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCoadministration\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\u003e0\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\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\u003eAdverse events ( AEs ) reported with SHC014748M alone included hypertriglyceridemia in two patients (10.5%, two events), hyperuricemia in one patient ( 5.3%, one event), increased blood bilirubin in two patients (10.5%, two events), decreased neutrophil count in one patient (5.3%, one event), supraventricular arrhythmia in two patients (10.5%, three events), and sinus bradycardia in two patients (10.5%, two events). AEs reported with continuous itraconazole administration included hypertriglyceridemia in one patient (5.3%, one event), increased blood bilirubin in two patients (10.5%, two events), increased total bile acids in one patient (5.3%, one event), and supraventricular arrhythmia in one patient (5.3%, one event).As shown in Table\u0026nbsp;\u003cspan refid=\"Tab8\" class=\"InternalRef\"\u003e8\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eTwo AEs were grade 2 in severity, occurring during phases 1 and 2: hypertriglyceridemia in two cases (10.5%, two episodes) and hypertriglyceridemia in one case (5.3%, one episode). All other adverse events were grade 1 in severity. No intervention was taken for any of the AEs reported by the subjects \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab9\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 9\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAdverse events related to the combination and monotherapy of SHC014748M with rifampicin\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\u003eTreatment Phase\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAdverse Events (AEs) n (%, events)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAdverse Drug Reactions (ADRs) n (%, events)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSerious AEs/ADRs\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLeading to Discontinuation\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSHC014748M\u0026thinsp;+\u0026thinsp;Rifampicin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10(50.0%, 18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9(45.0%, 17)\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSHC014748M Alone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4(20.0%, 4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3(15.0%, 3)\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRifampicin Alone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4(20.0%, 6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4(20.0%, 6)\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCoadministration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4(20.0%, 8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4(20.0%, 8)\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\u003e0\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\u003eAEs reported with SHC014748M monotherapy included increased blood bilirubin in one patient (5.0%, 1 episode), decreased neutrophil count in two patients (10.0%, 2 episodes), and sinus bradycardia in one patient (5.0%, 1 episode). AEs reported with continuous rifampicin therapy included increased blood bilirubin in three patients (15.0%, 3 episodes), positive urine leukocytes in two patients (10.0%, 2 episodes), and decreased lymphocyte count in one patient (5.0%, 1 episode). AEs reported with combined therapy included hypertriglyceridemia in one patient (5.0%, 1 episode), increased alanine aminotransferase in three patients (15.0%, 3 episodes), increased aspartate aminotransferase in two patients (10.0%, 2 episodes), increased C-reactive protein in one patient (5.0%, 1 episode), and chest discomfort in one patient (5.0%, 1 episode).As shown in Table\u0026nbsp;\u003cspan refid=\"Tab9\" class=\"InternalRef\"\u003e9\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSHC014748M is a highly selective PI3Kδ inhibitor. Similar drugs include the marketed Idelalisib, Duvelisib, and Copanlisib, as well as clinically tested drugs such as Zandelisib and Linperlisib \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Compared to these drugs, SHC014748M's greatest advantage lies in its higher selectivity (306-fold greater than PI3Kα for PI3Kδ and 69-fold greater than idelalisib), stronger in vitro activity, and improved efficacy in inducing tumor cell apoptosis. In early clinical trials, it has demonstrated no severe toxicity or adverse reactions with black box warnings, indicating better overall tolerability.\u003c/p\u003e\u003cp\u003eIn a drug interaction study between SHC014748M and itraconazole, co-administration of itraconazole (200 mg for 7 consecutive days) with SHC014748M did not significantly alter the peak time (T\u003csub\u003emax\u003c/sub\u003e) of SHC014748M ( median values were consistent with monotherapy). However, peak concentration (C\u003csub\u003emax\u003c/sub\u003e ) and exposure (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e) significantly increased, while clearance (CL/F) decreased. Furthermore, in a drug interaction study between SHC014748M and rifampicin, co-administration of rifampicin (600 mg for 5 consecutive days) with SHC014748M slightly shortened the peak time (T\u003csub\u003emax\u003c/sub\u003e) of SHC014748M ( median value was 85.7% of monotherapy), significantly decreased peak concentration (C\u003csub\u003emax\u003c/sub\u003e ) and exposure (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e), and significantly increased clearance (CL/F). Compared with SHC014748M alone, after 7 consecutive days of itraconazole administration\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, the geometric mean ratios of SHC014748M C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e (combination/single) were 145.3%, 215.2%, and 224.9%, respectively. Compared with SHC014748M alone, after 5 consecutive days of rifampicin administration, the geometric mean ratios of SHC014748M C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e (combination/single) were 52.1%, 22.8%, and 23.0%, respectively. These values are outside the 80.00%\u0026ndash;125.00% effect range. Therefore, significant drug-drug interactions exist between SHC014748M and the mutagenic agents itraconazole and rifampicin\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.The cytochrome P450 3A4/5 enzyme (CYP3A4/5) inhibitor itraconazole has a moderate inhibitory effect\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e on the metabolic elimination of SHC014748M23, and the cytochrome P450 3A4/5 enzyme (CYP3A4/5) inducer\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e rifampicin has a moderate induction effect on the metabolic elimination of SHC014748M24 .Co-administration of itraconazole with SHC014748M for 7 consecutive days increased the human exposure to SHC014748M by approximately 2.2 times that of SHC014748M alone, an increase in exposure that may be clinically significant. Conversely, co-administration of rifampicin with SHC014748M for 5 consecutive days reduced the human exposure to approximately 23% of SHC014748M alone, a significant decrease in exposure that may also be clinically significant.\u003c/p\u003e\u003cp\u003eIn this study, SHC014748M capsules were generally well tolerated. Compared with either SHC014748M capsules or itraconazole capsules alone, combined use of the two drugs increased only the incidence of elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST), there was no significant rise in the overall occurrence of other adverse reactions or in the occurrence of specific adverse reactions. Furthermore, compared with either SHC014748M capsules or rifampicin capsules alone, the combined use of the two drugs did not increase the overall incidence of adverse reactions or the incidence of individual adverse reactions\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e .\u003c/p\u003e\u003cp\u003eIn summary, this study aimed to investigate significant drug-drug interactions between SHC014748M and both itraconazole and rifampicin. Itraconazole significantly increased SHC014748M exposure, while rifampicin significantly decreased SHC014748M exposure. These interactions may have important clinical implications, necessitating careful evaluation and dose adjustment when coadministered. Furthermore, SHC014748M capsules were well tolerated in this study, with no new safety concerns identified.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePI3Kδ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePhosphoinositide 3-kinase delta\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCLL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eChronic lymphocytic leukemia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSLL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSmall lymphocytic lymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNHL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNon-Hodgkin lymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eiNHL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eindolent B-cell non-Hodgkin lymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCYP3A4/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCytochrome P450 3A4/5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDDI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003edrug–drug interaction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAUC₀-t\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eArea under the concentration-time curve from zero up to a definite time t\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAUC₀-∞\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCurve from zero up to ∞ with extrapolation of the terminal phase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCL/F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eApparent total plasma or serum clearance of drug after oral administration\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGCP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eGood Clinical Practice\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAdverse Event\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis clinical trial was approved by the Clinical Medical Research Ethics Committee of the First Affiliated Hospital of Bengbu Medical College. The study was conducted in strict accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) standards. Before any study-related procedures, the investigator explained to each prospective participant the nature, objectives, procedures, expected duration, potential risks, anticipated benefits, and possible discomforts of the trial, and written informed consent was obtained from all participants. The trial was registered with the China Drug Trials Registry (www.chinadrugtrials.org.cn, registration number CTR20201782, registration date: 27 August 2020).\u003cbr\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003cbr\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article and its supplementary information files.\u003cbr\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no conflict of interest.\u003cbr\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMajor Natural Science Research Projects of Universities in Anhui Province (No.2023AH040406; No.2023AH040290).\u003cbr\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJM.Z. conceived and designed the study, performed the experiments, analyzed the data, and wrote the original draft.MS.G curated the data and performed formal analysis.All authors read and approved the final manuscript.Besides all authors \u0026nbsp;declare no competing interests.\u003cbr\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was financially supported by Major Natural Science Research Projects of Universities in Anhui Province (No.2023AH040406; No.2023AH040290).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eFan L, Wang C, Zhao L, et al. SHC014748M, a novel selective inhi-bitor of PI3K\u0026delta;, demonstrates promising preclinical antitumor activity in B cell lymphomas and chronic lymphocytic leukemia. \u003cem\u003eNeoplasia.\u0026nbsp;\u003c/em\u003eDec 2020;22(12):714-724.\u003c/li\u003e\n \u003cli\u003eZhuang TZ, Zhang C, Strati P. SOHO State of the Art Updates and Next Questions | Novel Immunotherapy Combinations for the Treatment of Indolent B-Cell Lymphoma. \u003cem\u003eClin Lymphoma Myeloma Leuk.\u0026nbsp;\u003c/em\u003eJul 2025;25(7):455-464.\u003c/li\u003e\n \u003cli\u003eWillard P, McKay J, Yazbeck V. Role of antibody-based therapy in indolent non-Hodgkin\u0026apos;s lymphoma. \u003cem\u003eLeuk Res Rep.\u0026nbsp;\u003c/em\u003e2021;16:100275.\u003c/li\u003e\n \u003cli\u003eGuo F, Liu B, Li X, et al. Mass balance, metabolic disposition, and pharmacokinetics of a novel selective inhibitor of PI3K\u0026delta; [(14)C] SHC014748M in healthy Chinese subjects following oral administration. \u003cem\u003eCancer Chemother Pharmacol.\u0026nbsp;\u003c/em\u003eFeb 2023;91(2):143-156.\u003c/li\u003e\n \u003cli\u003ePafili K, Papanas N. Considerations for single- versus multiple-drug pharmacotherapy in the management of painful diabetic neuropathy. \u003cem\u003eExpert Opin Pharmacother.\u0026nbsp;\u003c/em\u003eNov 2021;22(16):2267-2280.\u003c/li\u003e\n \u003cli\u003eZhu V, Burhenne J, Weiss J, et al. Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers. \u003cem\u003eFront Pharmacol.\u0026nbsp;\u003c/em\u003e2023;14:1128547.\u003c/li\u003e\n \u003cli\u003eZhu J, Jia L, Jiang Y, et al. Integrated molecular modeling techniques to reveal selective mechanisms of inhibitors to PI3K\u0026delta; with marketed Idelalisib. \u003cem\u003eChem Biol Drug Des.\u0026nbsp;\u003c/em\u003eJun 2021;97(6):1158-1169.\u003c/li\u003e\n \u003cli\u003eZoulikha M, He W. Targeted Drug Delivery for Chronic Lymphocytic Leukemia. \u003cem\u003ePharm Res.\u0026nbsp;\u003c/em\u003eMar 2022;39(3):441-461.\u003c/li\u003e\n \u003cli\u003eZuo T, Liu Y, Duan M, et al. Platelet-derived growth factor PDGF-AA upregulates connexin 43 expression and promotes gap junction formations in osteoblast cells through p-Akt signaling. \u003cem\u003eBiochem Biophys Rep.\u0026nbsp;\u003c/em\u003eJul 2023;34:101462.\u003c/li\u003e\n \u003cli\u003eZinzani PL, Wang H, Feng J, et al. CHRONOS-4: phase 3 study of copanlisib plus rituximab-based immunochemotherapy in relapsed indolent B-cell lymphoma. \u003cem\u003eBlood Adv.\u0026nbsp;\u003c/em\u003eSep 24 2024;8(18):4866-4876.\u003c/li\u003e\n \u003cli\u003eZhou M, Hu C, Yin Y, et al. Experimental Evolution of Multidrug Resistance in Neurospora crassa under Antifungal Azole Stress. \u003cem\u003eJ Fungi (Basel).\u0026nbsp;\u003c/em\u003eFeb 18 2022;8(2).\u003c/li\u003e\n \u003cli\u003eZuo D, Lv L, Ren H, Sun H. Effects of polyphenols extracted from Keemun black tea on CYP450s activity and molecular mechanisms. \u003cem\u003eFood Sci Nutr.\u0026nbsp;\u003c/em\u003eOct 2024;12(10):7306-7315.\u003c/li\u003e\n \u003cli\u003eWang K, Ding J, Li X, et al. Effects of itraconazole and rifampicin on the pharmacokinetics and safety of youkenafil, a novel phosphodiesterase type 5 inhibitor, in healthy Chinese subjects. \u003cem\u003eEur J Pharm Sci.\u0026nbsp;\u003c/em\u003eAug 1 2022;175:106213.\u003c/li\u003e\n \u003cli\u003eZou Y, Xu W, Li J. Chimeric antigen receptor-modified T cell therapy in chronic lymphocytic leukemia. \u003cem\u003eJ Hematol Oncol.\u0026nbsp;\u003c/em\u003eNov 20 2018;11(1):130.\u003c/li\u003e\n \u003cli\u003eLi H, Yang Y, Wang P, et al. [Clinical and genetic analysis of a case of Triadin knockout syndrome due to variant of TRDN gene and a literature review]. \u003cem\u003eZhonghua Yi Xue Yi Chuan Xue Za Zhi.\u0026nbsp;\u003c/em\u003eNov 10 2024;41(11):1323-1329.\u003c/li\u003e\n \u003cli\u003ePan L, Xiao X, Liu S, Peng S. An Integration Framework of Secure Multiparty Computation and Deep Neural Network for Improving Drug-Drug Interaction Predictions. \u003cem\u003eJ Comput Biol.\u0026nbsp;\u003c/em\u003eSep 2023;30(9):1034-1045.\u003c/li\u003e\n \u003cli\u003eZyryanov S, Bondareva I, Butranova O, Kazanova A. Population PK/PD modelling of meropenem in preterm newborns based on therapeutic drug monitoring data. \u003cem\u003eFront Pharmacol.\u0026nbsp;\u003c/em\u003e2023;14:1079680.\u003c/li\u003e\n \u003cli\u003eZwittnig K, Kirnbauer B, Truschnegg A, et al. Effectiveness of platelet-rich fibrin in third molar extractions: a randomized controlled split-mouth study. \u003cem\u003eClin Oral Investig.\u0026nbsp;\u003c/em\u003eOct 29 2024;28(11):615.\u003c/li\u003e\n \u003cli\u003eZhou T, Xu W, Zhang W, et al. Preclinical profile and phase I clinical trial of a novel androgen receptor antagonist GT0918 in castration-resistant prostate cancer. \u003cem\u003eEur J Cancer.\u0026nbsp;\u003c/em\u003eJul 2020;134:29-40.\u003c/li\u003e\n \u003cli\u003eWitkowska M, Majchrzak A, Robak P, Wolska-Washer A, Robak T. Metabolic and toxicological considerations for phosphoinositide 3-kinase delta inhibitors in the treatment of chronic lymphocytic leukemia. \u003cem\u003eExpert Opin Drug Metab Toxicol.\u0026nbsp;\u003c/em\u003eSep 2023;19(9):617-633.\u003c/li\u003e\n \u003cli\u003eKucukkaya IC, Gulsever CI, Dolas I, et al. First case of Rhinocladiella mackenziei brain abscess in Turkey: Case report and review of the literature. \u003cem\u003eMycoses.\u0026nbsp;\u003c/em\u003eSep 2023;66(9):755-766.\u003c/li\u003e\n \u003cli\u003eMukonzo JK, Kengo A, Kutesa B, et al. Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB-rifampicin sensitivity among Ugandan patients. \u003cem\u003eTrans R Soc Trop Med Hyg.\u0026nbsp;\u003c/em\u003eFeb 7 2020;114(2):107-114.\u003c/li\u003e\n \u003cli\u003eZubiaur P, Benedicto MD, Villapalos-Garc\u0026iacute;a G, et al. SLCO1B1 Phenotype and CYP3A5 Polymorphism Significantly Affect Atorvastatin Bioavailability. \u003cem\u003eJ Pers Med.\u0026nbsp;\u003c/em\u003eMar 13 2021;11(3).\u003c/li\u003e\n \u003cli\u003eZhang Y, Wang Z, Wang Y, et al. CYP3A4 and CYP3A5: the crucial roles in clinical drug metabolism and the significant implications of genetic polymorphisms. \u003cem\u003ePeerJ.\u0026nbsp;\u003c/em\u003e2024;12:e18636.\u003c/li\u003e\n \u003cli\u003eŻychowska M, Żychowska M. No evidence for association between cutaneous lichen planus and hepatitis B and C virus infection in south Poland - a case-control study. \u003cem\u003eInt J Dermatol.\u0026nbsp;\u003c/em\u003eJun 2020;59(6):698-703.\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":"SHC014748M, CYP3A4/5, Drug-drug interactions, Tolerability","lastPublishedDoi":"10.21203/rs.3.rs-7397648/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7397648/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u0026nbsp;\u003c/strong\u003e To evaluate\u0026nbsp;the pharmacokinetics\u0026nbsp;of SHC014748M\u0026nbsp;under\u0026nbsp;the influence of different drugs\u0026nbsp;.\u0026nbsp;SHC014748M, a selective PI3Kδ inhibitor, has shown potential therapeutic value in patients with CLL/SLL and NHL in clinical studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eThis study employed a single-center, two-period, open-label, sequential-dose design.\u0026nbsp;Key pharmacokinetic parameters were calculated using non-compartmental analysis using WinNonlin software (version 8.2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eCoadministration of SHC014748M with CYP3A4/5 inhibitors or inducers significantly affected the maximum plasma concentration (C\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;)\u0026nbsp;, the area under the curve at the cutoff time point (AUC\u003csub\u003e0-t\u003c/sub\u003e\u0026nbsp;), and the area under the curve extending to infinity (AUC\u003csub\u003e0-∞\u003c/sub\u003e). This drug-drug interaction demonstrated statistically significant differences in pharmacokinetic parameters (90% confidence interval for the geometric mean ratio outside the 80.00% to 125.00% equivalence range).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u0026nbsp;\u0026nbsp;Since SHC014748M is a substrate of CYP3A4/5 metabolizers, it may cause drug-drug interactions with CYP3A4/5 inhibitors and inducers during clinical use. In this study, SHC014748M capsules showed good tolerability.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e Registration authority: China Drug Trials, TRN:CTR20201782, Registration date: August 27, 2020.\u003c/p\u003e","manuscriptTitle":"Drug-drug interaction study between SHC014748M and itraconazole and rifampicin","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-22 19:21:35","doi":"10.21203/rs.3.rs-7397648/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":"a69dcb34-fb27-4c81-b34f-ed1ff8d2942b","owner":[],"postedDate":"October 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-12T00:54:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-22 19:21:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7397648","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7397648","identity":"rs-7397648","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}