Impact of Steady State Cobicistat and Darunavir/Cobicistat on the Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants (Rivaroxaban, Apixaban) in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Apparent Oral Clearance (CL/F) for Rivaroxaban
研究概览
简要总结
Background:
Rivaroxaban and apixaban are blood thinners. People with HIV may need to take them to treat or prevent blood clots. The anti-HIV drug darunavir (DRV) can increase the amount of these blood thinners in the body. This can cause bleeding or other health problems. The drug cobicistat (COBI) is used to help anti-HIV drugs work better. Researchers want to give healthy people DRV combined with COBI to learn how it affects rivaroxaban or apixaban blood levels.
Objective:
To test blood levels of rivaroxaban or apixaban when taken with COBI and DRV/COBI.
Eligibility:
Healthy volunteers ages 18-65
Design:
Participants will be screened with:
Medical history
Physical exam
Fasting blood and urine tests. (Urine tests will be performed in females of child-bearing potential only)
Participants will have 8 visits; 3 are long (about 10-12 hours) and 5 are about 1 hour. They include:
Baseline and final visits:
Fasting blood and urine tests
Day 1 visit (long day):
Fasting blood and urine tests
Catheter placement: A needle will insert a small tube into the participant's arm vein. Blood will be drawn up to 10 times.
Dose of rivaroxaban or apixaban
Day 2 visit (short day):
Fasting blood tests
Dose of COBI
Participants will receive a bottle containing COBI tablets to take at home.
Day 7 (long day):
Fasting blood and urine tests
Catheter placement: A needle will insert a small tube into the participant's arm vein. Blood will be drawn up to 10 times.
Dose of rivaroxaban or apixaban
Dose of COBI
Day 8 (short day):
Fasting blood tests
Dose of DRV/COBI Participants will receive a bottle containing DRV/COBI tablets to take at home.
Day 13 (long day):
Fasting blood and urine tests
Catheter placement: A needle will insert a small tube into the participant s arm vein. Blood will be drawn up to 10 times.
Dose of rivaroxaban or apixaban
Dose of DRV/COBI
Day 14 (short day):
Fasting blood tests
Participants will take COBI tablets daily at home on days 3-6, and DRV/COBI on days 9 -12 during the study. They will record doses and side effects.
During the study, participants cannot:
Take most medications.
Drink alcohol, smoke, or vape
Engage in activities such as contact and extreme sports
详细描述
Rivaroxaban is a direct oral anticoagulant (DOAC) used for the prevention and treatment of various thromboembolic disorders. Predictable pharmacokinetic (PK) and pharmacodynamic (PD) properties, coupled with a few drug drug and food-drug interactions, distinguishes DOACs from a traditionally used anticoagulant, warfarin, allowing fixed dosing without routine coagulation monitoring. Patients with human immunodeficiency virus (HIV) are living as long as their HIV negative counterparts due to safe and efficacious antiretroviral therapy (ART). Persons with HIV are at higher risk for thromboembolic events and DOACs are a feasible option for anticoagulation in this population. However, there is a lack of drug interaction and safety data currently on the co-administration cobicistat (COBI)-boosted antiretroviral (ARV) regimens with rivaroxaban. Rivaroxaban is metabolized by cytochrome P450 isozyme (CYP) 3A4 and its absorption is modulated by permeability glycoprotein (P-gp), both of which are inhibited by the PK booster COBI. It is therefore possible that plasma concentrations of rivaroxaban may be significantly increased when co-administered together with COBI. This is of clinical concern as increased anticoagulant exposure may result in bleeding without the security of routine clinical monitoring. The purpose of this study is to determine the effects of steady state concentrations of COBI and darunavir (DRV)/COBI on the PK and PD of single oral doses of rivaroxaban.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Pharmacokinetic study in healthy volunteers
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
干预措施: Cobicistat (Drug)
Pharmacokinetic study in healthy volunteers
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
干预措施: Darunavir/Cobicistat (Drug)
Pharmacokinetic study in healthy volunteers
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
干预措施: Rivaroxaban (Drug)
结局指标
主要结局
Apparent Oral Clearance (CL/F) for Rivaroxaban
时间窗: Up to 24 hours postdose on days 1, 7, and 13
Apparent oral clearance (CL/F) for Rivaroxaban following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 was analyzed using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA). CL/F was calculated as 10 mg ÷ AUC0-tau for rivaroxaban.
Area Under the Concentration Versus Time Curve (AUC0-∞) for Rivaroxaban
时间窗: Total drug exposure at time point zero to infinity on days 1, 7, & 13
Area under the concentration versus time curve from 0 to infinity (AUC0-∞) following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 to measure the total drug exposure was analyzed by the linear up/log down trapezoidal rule using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA).
Area Under the Concentration Versus Time Curve (AUC0-24hr) for Rivaroxaban
时间窗: 0 to 24 hours postdose on days 1, 7, and 13
Area under the concentration versus time curve from (AUC0-24hr) following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 to measure total drug exposure was analyzed by the linear up/log down trapezoidal rule using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA).
Maximum Total Plasma Concentration (Cmax) for Rivaroxaban
时间窗: Up to 24 hours postdose on days 1, 7, and 13
Maximum total plasma concentration (Cmax) following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 was analyzed using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA). Cmax for rivaroxaban was obtained directly by visual inspection of the plasma concentration versus time over 24 hours postdose.
Time to Maximum Plasma Concentration (Tmax) for Rivaroxaban
时间窗: Up to 24 hours postdose on days 1, 7, and 13
Time to maximum plasma concentration for Rivaroxaban following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 was analyzed using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA). Tmax for rivaroxaban was obtained directly by visual inspection of the plasma concentration versus time over 24 hours postdose.
Terminal Elimination Half-life (t½) for Rivaroxaban
时间窗: Up to 24 hours postdose on days 1, 7, and 13
Terminal elimination half-life (t½) for Rivaroxaban following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 was analyzed using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA). The apparent elimination rate constant (λZ) was determined by calculating the absolute value of the slope of the log-linear regression of at least 3 points of the plasma concentration-time plot. The t½ was calculated as 0.693/apparent elimination rate constant (λZ).
Apparent Volume of Distribution (V/F) for Rivaroxaban
时间窗: Up to 24 hours postdose on days 1, 7, and 13
Apparent volume of distribution (V/F) for Rivaroxaban following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 was analyzed using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA).
Minimum Total Plasma Concentration (Cmin) for Rivaroxaban
时间窗: Up to 24 hours postdose on days 1, 7, and 13
Minimum total plasma concentration (Cmin) for Rivaroxaban following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 was analyzed using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA). Cmin for rivaroxaban was obtained directly by visual inspection of the plasma concentration versus times over 24 hours postdose.
次要结局
未报告次要终点