A Phase I, Open-label, Two-part, Fixed-sequence Drug Interaction Study to Evaluate the Effects of Concomitant Use of the CYP3A4 Inhibitor Itraconazole or the CYP3A4 Inducer Rifampin on the Pharmacokinetics of Rocbrutinib in Healthy Subjects
概览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- Guangzhou Lupeng Pharmaceutical Company LTD.
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- AUC
概览
简要总结
This is a phase I, open-label, two-part, fixed-sequence drug interaction study conducted to evaluate the effects of concomitant use of the potent CYP3A4 inhibitor itraconazole or the CYP3A4 inducer rifampin on the pharmacokinetics of Rocbrutinib in healthy subjects.
详细描述
This study evaluated the changes in the pharmacokinetic profiles of Rocbrutinib under maximal CYP3A inhibition and induction conditions by investigating the co-administration of Rocbrutinib with potent CYP3A inhibitors or inducers at steady state, compared with Rocbrutinib administered alone.
To assess the potential clinical inhibition of OATP1B by Rocbrutinib, blank plasma samples were collected prior to Rocbrutinib administration and 24-hour plasma samples were collected post-administration. The concentration of coproporphyrin I (CP-I) in these samples was detected and analyzed.
Furthermore, the effect of P-gp inhibitors on the drug absorption of Rocbrutinib (when acting as a substrate) was evaluated by investigating two scenarios: co-administration of a single dose of Rocbrutinib with a single dose of the P-gp inhibitor rifampicin, and co-administration of a single dose of Rocbrutinib with the P-gp inhibitor itraconazole at steady state.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Subjects had no history of serious digestive system (such as inflammatory bowel disease, chronic diarrhea, Crohn's disease, autonomic dysfunction affecting gastric emptying), nervous system, cardiovascular system, genitourinary system, respiratory system, metabolic and endocrine system, musculoskeletal system, hematologic system diseases, or tumors
- •Subjects must agree to complete abstinence or use effective physical contraception (including sterilization, intrauterine device or barrier contraception) from the time of signing the informed consent form until 90 days after the last dose of medication, and have no plans to donate sperm or eggs during this period; if female subjects are using hormonal contraceptives, they must stop using them \>14 days before the first dose and use at least one of the above contraceptive methods.
- •Must be between 18 and 45 years old (inclusive) and be male or female when signing the informed consent form.
- •Males weighing ≥50.0 kg or females weighing ≥45.0 kg, with a Body Mass Index (BMI) between 18.0 and 28.0 kg/m² (inclusive). BMI = weight (kg) / height² (m²).
- •Able to understand and comply with the requirements of the research plan.
- •Voluntarily participate in this study and sign the informed consent form.
排除标准
- •Abnormalities in screening tests, such as vital signs, physical examination, or laboratory tests are clinically significant and may increase the risk of participants participating in the study or affect the scientific validity of the study.
- •Abnormal electrocardiogram or myocardial enzyme levels that are clinically significant as determined by a clinician include, but are not limited to: QTcF ≥ 450 ms (corrected using the Fridricia formula, QTcF = QT/RR1/3, RR = 60/HR), etc.
- •The test results for at least one of the following are positive: hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody, and syphilis-specific antibody.
- •Patients who have taken the investigational drug within 4 weeks prior to or are required to take any drugs known to alter liver enzyme activity during the study period.
- •The patient must have used any systemic medications (including any vaccines, prescription drugs, over-the-counter drugs, and traditional Chinese medicines), special medical purpose foods, or health supplements within two weeks prior to taking the investigational drug.
- •Had consumed foods known to alter liver enzyme activity (such as grapefruit, star fruit, dragon fruit, and their fruit juices) and tobacco (including e-cigarettes) within one week prior to taking the investigational drug.
- •Consume any food or beverage containing caffeine, tea, alcohol, or xanthine within 24 hours prior to taking the investigational drug.
- •Difficulty swallowing or any condition that affects drug absorption, distribution, metabolism, or excretion.
- •Women with childbearing potential who have a positive pregnancy test result or who are currently breastfeeding.
- •Those with a history of smoking (smoking more than 5 cigarettes/day within 3 months prior to screening) or who tested positive for nicotine screening.
研究组 & 干预措施
Inhibitor Group
The Inhibitor Group was designed to investigate the drug-drug interaction between Rocbrutinib and itraconazole (a potent CYP3A inhibitor and P-gp inhibitor). Itraconazole is a recommended potent index CYP3A inhibitor for clinical studies in the ICH-M12 Guideline on Drug Interactions. In accordance with the recommendations in an industry white paper (CPT Pharmacometrics Syst Pharmacol. 2019 Aug 7;8(9):685-695), an initial loading dose of 400 mg followed by a maintenance dose of 200 mg once daily (QD) was selected as the itraconazole dosing regimen in this study.
Based on the predicted proportion of plasma exposure of metabolites from previous mass balance studies and combined with the previously established safety profile of Rocbrutinib, potent CYP3A inhibition is expected to potentially significantly increase the plasma concentration of Rocbrutinib when co-administered. Therefore, the clinically confirmed minimum effective dose of Rocbrutinib (100 mg) was chosen for co-administration
干预措施: Rocbrutinib tablets (Drug)
Inhibitor Group
The Inhibitor Group was designed to investigate the drug-drug interaction between Rocbrutinib and itraconazole (a potent CYP3A inhibitor and P-gp inhibitor). Itraconazole is a recommended potent index CYP3A inhibitor for clinical studies in the ICH-M12 Guideline on Drug Interactions. In accordance with the recommendations in an industry white paper (CPT Pharmacometrics Syst Pharmacol. 2019 Aug 7;8(9):685-695), an initial loading dose of 400 mg followed by a maintenance dose of 200 mg once daily (QD) was selected as the itraconazole dosing regimen in this study.
Based on the predicted proportion of plasma exposure of metabolites from previous mass balance studies and combined with the previously established safety profile of Rocbrutinib, potent CYP3A inhibition is expected to potentially significantly increase the plasma concentration of Rocbrutinib when co-administered. Therefore, the clinically confirmed minimum effective dose of Rocbrutinib (100 mg) was chosen for co-administration
干预措施: Itraconazole capsules (Drug)
Inducer Group
The Inducer Group was designed to investigate the drug-drug interaction between Rocbrutinib and rifampicin (a potent CYP3A inducer and P-gp inhibitor). Rifampicin is a recommended potent index CYP3A inducer for clinical studies in the ICH-M12 Guideline on Drug Interactions. The maximum dose and shortest dosing interval in its clinically recommended regimen is 600 mg once daily (QD), so 600 mg QD was selected as the rifampicin dosing regimen in this study.
Potent CYP3A inducers are expected to either decrease the plasma concentration of Rocbrutinib or have no significant effect on it. Therefore, the clinically recommended higher dose of Rocbrutinib (200 mg) was chosen for co-administration with rifampicin in the Inducer Group.
In Cycle 2, Rocbrutinib administration was initiated on Day 10 (the 7th day after the start of continuous rifampicin dosing) and continued until the day before the last blood collection for Rocbrutinib (Day 12), which was sufficient to cover the in vivo drug meta
干预措施: Rocbrutinib tablets (Drug)
Inducer Group
The Inducer Group was designed to investigate the drug-drug interaction between Rocbrutinib and rifampicin (a potent CYP3A inducer and P-gp inhibitor). Rifampicin is a recommended potent index CYP3A inducer for clinical studies in the ICH-M12 Guideline on Drug Interactions. The maximum dose and shortest dosing interval in its clinically recommended regimen is 600 mg once daily (QD), so 600 mg QD was selected as the rifampicin dosing regimen in this study.
Potent CYP3A inducers are expected to either decrease the plasma concentration of Rocbrutinib or have no significant effect on it. Therefore, the clinically recommended higher dose of Rocbrutinib (200 mg) was chosen for co-administration with rifampicin in the Inducer Group.
In Cycle 2, Rocbrutinib administration was initiated on Day 10 (the 7th day after the start of continuous rifampicin dosing) and continued until the day before the last blood collection for Rocbrutinib (Day 12), which was sufficient to cover the in vivo drug meta
干预措施: Rifampicin capsules (Drug)
结局指标
主要结局
AUC
时间窗: Until 72 hours or 96 hours after Rocbrutinib
Area under the curve
Cmax
时间窗: Until 72 hours or 96 hours after Rocbrutinib
Plasma peak concentration of Rocbrutinib
t1/2
时间窗: Until 72 hours or 96 hours after Rocbrutinib
Terminal phase half-life of Rocbrutinib
次要结局
- Plasma coprophyrin I (CP-I) concentration(Baseline and 24 hours after Rocbrutinib)
- Adverse events(Up to 20 days after Rocbrutinib)