Impact of Steady State Cobicistat and Darunavir/Cobicistat on the Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants (Rivaroxaban, Apixaban) in Health Volunteers
- Conditions
- Healthy Volunteers
- Interventions
- Registration Number
- NCT03864406
- Brief Summary
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
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 12
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Pharmacokinetic study in healthy volunteers Cobicistat 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. Pharmacokinetic study in healthy volunteers Darunavir/Cobicistat 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. Pharmacokinetic study in healthy volunteers Rivaroxaban 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.
- Primary Outcome Measures
Name Time Method Apparent Oral Clearance (CL/F) for Rivaroxaban 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 (AUC0-24hr) for Rivaroxaban 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 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 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 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 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 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.
Area Under the Concentration Versus Time Curve (AUC0-∞) for Rivaroxaban 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).
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States