Influence of Autoinhibition/Autoinduction and CYP2B6 Genetic Variations on CYP2B6 Activity and Drug Interactions in Healthy Volunteers
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- Efavirenz AUC0-inf (Single Dose) and AUC0-24(Multiple Dose)
研究概览
简要总结
The CYP2B6 enzyme metabolizes a growing number of clinically important drugs such as the anti-HIV drug efavirenz, but its activity in the liver is highly variable, which may lead to failure of therapy or toxicity and unpredictable drug interactions. Genetic and several nongenetic factors affect the activity of CYP2B6. The goal of this study is to determine the impact of simultaneous autoinhibition/autoinduction and CYP2B6 genetics on CYP2B6 activity, efavirenz exposure and efavirenz-mediated drug interactions. The pharmacokinetics and drug interactions will be determined on three occasions in a total of 60 healthy volunteers. The whole study will have 4 phases. A) Phase 1 (baseline control): using selective probe substrates, the baseline activities of CYP2B6 (bupropion), CYP2C8 (montelukast) and OATP1B1 (rosuvastatin) are determined. B) Phase 2 (inhibition): the metabolism and pharmacokinetics of a single 600 mg oral dose of efavirenz) and the activities of CYP2B6, CYP2C8 and OATP1B1 (inhibition) are determined. C) Phase 3 (treatment phase): After completing phase 2, subjects take 600 mg/day efavirenz at home for 17 days. C) Phase 4 (induction and inhibition): At the end of phase 3, steady state metabolism and pharmacokinetics of efavirenz and the activities of CYP2B6, CYP2C8 and OATP1B1 will be determined. Efavirenz serves as a model substrate, inhibitor and inducer of CYP2B6 (and other drug disposition proteins). Bupropion 4-hydroxylation is an alternative in vivo probe of CYP2B6 activity and will be studied here in addition to the metabolism and pharmacokinetics of efavirenz.
详细描述
Schedule of assessment
PHASE 1 (CONTROL PHASE)
Phase 1 (day 1 to day 4): baseline (control) activities of CYP2B6, CYP2C8 and OATP1B1 will be measured using selective probe substrates. Eligible subjects will receive simultaneously a single 100 mg dose of bupropion (CYP2B6), a single 10 mg dose montelukast (CYP2C8) and a single 5 mg dose of rosuvastatin (OATP1B1) by mouth on empty stomach together at least 10 days before phase 2. Frequent plasma samples will be collected for 72 hours and urine for 48 hours after dosing. Safety assessment will be made for the first 24 hours. Phase 1 is completed after the last blood draw on day 4 (72 hours).
PHASE 2 (INHIBITION PHASE)
In phase 2 (days 11 to 16), the metabolism and pharmacokinetics of a single 600 mg oral dose efavirenz will be determined along with the activities of CYP2B6, CYP2C8 and OATP1B1. Subjects receive a single 600 mg oral dose of efavirenz and blood samples will be obtained at 30 min and 1 hour. Immediately after the 1 hour blood draw, the three probe drugs (10 mg montelukast, 100 mg bupropion, and 5 mg rosuvastatin) will be administered simultaneously. Frequent plasma samples will be collected for 120 hours and urine for 48 hours after efavirenz dosing. Safety assessment will be made for the first 24 hours. Phase 2 is completed after the last blood draw on day 16 (120 hours). Note: The additional time points (compared to phase 1) are needed because of the long elimination half-life of efavirenz.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 49 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
CYP2B6
This is a fixed-order, open label prospective cohort study to determine: a) the contribution of CYP2B6 autoinhibition/autoinduction processes to variable CYP2B6 activity and efavirenz exposure; b) the impact of CYP2B6 genetic variants on these processes; and c) drug interactions that ensue.
Included drugs:
Efavirenz (600mg) - The volunteers will receive it in two of three inpatient visits and also during 17 days at home
Bupropion (100mg), Montelukast (10mg) and Rosuvastatin (5mg) - These drugs will be administrated on 3 occasions (at the begging each inpatient visit of Phase 1, 2 and 4).
干预措施: Efavirenz (Drug)
CYP2B6
This is a fixed-order, open label prospective cohort study to determine: a) the contribution of CYP2B6 autoinhibition/autoinduction processes to variable CYP2B6 activity and efavirenz exposure; b) the impact of CYP2B6 genetic variants on these processes; and c) drug interactions that ensue.
Included drugs:
Efavirenz (600mg) - The volunteers will receive it in two of three inpatient visits and also during 17 days at home
Bupropion (100mg), Montelukast (10mg) and Rosuvastatin (5mg) - These drugs will be administrated on 3 occasions (at the begging each inpatient visit of Phase 1, 2 and 4).
干预措施: Bupropion (Drug)
CYP2B6
This is a fixed-order, open label prospective cohort study to determine: a) the contribution of CYP2B6 autoinhibition/autoinduction processes to variable CYP2B6 activity and efavirenz exposure; b) the impact of CYP2B6 genetic variants on these processes; and c) drug interactions that ensue.
Included drugs:
Efavirenz (600mg) - The volunteers will receive it in two of three inpatient visits and also during 17 days at home
Bupropion (100mg), Montelukast (10mg) and Rosuvastatin (5mg) - These drugs will be administrated on 3 occasions (at the begging each inpatient visit of Phase 1, 2 and 4).
干预措施: Rosuvastatin (Drug)
CYP2B6
This is a fixed-order, open label prospective cohort study to determine: a) the contribution of CYP2B6 autoinhibition/autoinduction processes to variable CYP2B6 activity and efavirenz exposure; b) the impact of CYP2B6 genetic variants on these processes; and c) drug interactions that ensue.
Included drugs:
Efavirenz (600mg) - The volunteers will receive it in two of three inpatient visits and also during 17 days at home
Bupropion (100mg), Montelukast (10mg) and Rosuvastatin (5mg) - These drugs will be administrated on 3 occasions (at the begging each inpatient visit of Phase 1, 2 and 4).
干预措施: Montelukast (Drug)
结局指标
主要结局
Efavirenz AUC0-inf (Single Dose) and AUC0-24(Multiple Dose)
时间窗: Single dose pharmacokinetics (PK) versus multiple doses (after 17 day pretreatment) PK (total 38 days for each subject)
After the samples collection, blood from phase 2 and phase 4 were used to perform the quantification of Efavirenz in plasma. The composite of the efavirenz concentration (blood collection between 0 to 120 hrs) were used to calculate the area under the plasma concentration time curve (AUC0-inf for single dose and AUC0-24 for multiple dose) of efavirenz.
次要结局
未报告次要终点
研究者
Zeruesenay Desta
Research Professor
Indiana University