Impact of Steady State Cobicistat and Darunavir/Cobicistat on the Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants (Rivaroxaban, Apixaban) in Health Volunteers

Impact of Steady State Cobicistat and Darunavir/Cobicistat on the Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants (Rivaroxaban, Apixaban) in Healthy Volunteers

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

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Cobicistat; Drug: Darunavir/Cobicistat; Drug: Rivaroxaban

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Colleen M Hadigan, M.D.; Phone Number: (301) 594-5754; Email: hadiganc@niaid.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

A subject will be considered eligible for this study only if all of the following criteria are met:

• Adults between the ages of 18 to 65 years.
• Body mass index between 18 to 30 kg/M(2).
• Judged to be healthy based on medical history, physical examination, vital signs and clinical laboratory tests (liver function tests (LFTs: alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin less than or equal to upper limit of normal (ULN) (with the exception of participants with Gilbert's syndrome), albumin within normal limits (WNL)], eGFR > 90 mL/min/1.73 m(2), PLT>150,000/microL, hemoglobin (Hgb) greater than or equal to 12 g/dL, activated partial thromboplastin time (aPTT) less than or equal to ULN, partial thromboplastin time (PTT) less than or equal to ULN, international normalized ratio (INR) less than or equal to ULN.
• Subject agrees to storage of specimens for future research.
• Negative serum or urine pregnancy test for females of child-bearing potential.
• For female subjects, willing to avoid pregnancy by (a) practicing abstinence or (b) using effective non-hormonal and/or barrier methods of birth control, as well as avoid breast feeding or providing breast milk to infant during the study period. (baseline visit up to end of study day 20 plus minus 3)
• Willing to avoid engaging in activities such as contact sports, including extreme sports, that may increase the risk of bleeding through body injury or bruising, during the study period (baseline visit up to end of study day 20 plus minus 3)
• Willingness to forgo drinking alcohol during the study period (baseline visit up to end of study day 20 plus minus 3)
• Able to provide consent.

EXCLUSION CRITERIA:

A subject will be ineligible for this study if one, or more, of the following criteria are met:

• HIV infection, as determined by standard serologic or virologic assays for HIV infection.
• Laboratory evidence of active or chronic hepatitis A, B or C infection.

• History or presence of any of the following:

  • any major medical conditions that requires daily frequent medication or potentially impairs medication absorption, metabolism and elimination
  • any other condition that may interfere with the interpretation of the study results, or not be in the best interest of the subject in the opinion of the Investigator.
• Current participation in an ongoing investigational drug protocol or use of any investigational drug within 30 days (based on last dose received) prior to receipt of any study drugs/medications.

• History or presence of the following:

  • bleeding/hematologic disorders (e.g., anemia, hemophilia, etc.),
  • serious/major bleeding event (intracranial, gastrointestinal (GI), as assessed by subject interview), or
  • current increased risk of bleeding
  • for female subjects, menorrhagia
• Planned invasive or surgical procedure within (prior to or following) 28 days of study participation.
• Therapy with any prescription, over-the-counter, herbal, or holistic medications, including hormonal contraceptives by any route, within 5 half-lives of the agent prior to receipt of any study medications will not be permitted with the following exception:

Intermittent or short-course therapy (<14 days) with prescription, vaccines or over-the-counter medications will be reviewed by investigators on a case-by-case basis for potential drug interactions.

• Inability to obtain venous access for sample collection.
• Inability to swallow whole capsules and/or tablets.
• Pregnant female.
• Breastfeeding female.
• The presence of persistent diarrhea or malabsorption that could interfere with the subject's ability to absorb drugs.
• Illicit drug or alcohol use
• Use of nicotine-containing tobacco products, including cigarettes, vaping and chewing tobacco.
• Known hypersensitivity to rivaroxaban, apixaban, COBI or DRV.
• History of documented hypersensitivity to sulfa allergy.
• Organ transplant recipient.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: Cobicistat; Each tablet of Tybost contains 150 mg of cobicistat.; Other Names: Tybost; Drug: Darunavir/Cobicistat; Each tablet of Prezcobix contains 800 mg of darunavir and 150 mg of cobicistat.; Other Names: Prezcobix; Drug: Rivaroxaban; Each tablet of Xarelto contains 10 mg of rivaroxaban.; Other Names: Xarelto

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration Versus Time Curve (AUC0-∞) for Rivaroxaban	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).	Total drug exposure at time point zero to infinity on days 1, 7, & 13
Area Under the Concentration Versus Time Curve (AUC0-24hr) for Rivaroxaban	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).	0 to 24 hours postdose on days 1, 7, and 13
Maximum Total Plasma Concentration (Cmax) for Rivaroxaban	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.	Up to 24 hours postdose on days 1, 7, and 13
Time to Maximum Plasma Concentration (Tmax) for Rivaroxaban	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.	Up to 24 hours postdose on days 1, 7, and 13
Terminal Elimination Half-life (t½) for Rivaroxaban	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).	Up to 24 hours postdose on days 1, 7, and 13
Apparent Oral Clearance (CL/F) for Rivaroxaban	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.	Up to 24 hours postdose on days 1, 7, and 13
Apparent Volume of Distribution (V/F) for Rivaroxaban	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).	Up to 24 hours postdose on days 1, 7, and 13
Minimum Total Plasma Concentration (Cmin) for Rivaroxaban	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.	Up to 24 hours postdose on days 1, 7, and 13

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
(2) AEs and abnormal laboratory values, as graded according to the DAIDS AE table and Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Trials AE table (total bilirubin only).	(2) To evaluate the safety of coadministration of oral anticoagulants (rivaroxaban, apixaban) alone and in combination with cobicistat or darunavir/cobicistat in healthy volunteers through documentation of adverse events (AEs) according to the Division of AIDS (DAIDS) AE Table for Grading the Severity of Adult and Pediatric Adverse Events Table and the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Trials AE table (total bilirubin only).	Days 1, 7 and 13 at the following times: Arm A (Rivaroxaban): times 0 (predose), 1, 2, 3, 4, 6, 8, 10 and 24 hours post-dose. Arm B (Apixaban): times 0 (predose), 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
(1) Area under the effect curve for factor Xa, aPTT and PT from 0 to 24 hours (AUEC0-24), and the maximum effect ratio over baseline (ERmax),	(1) To characterize the PD (anti FXa, aPTT, PT/INR) of oral anticoagulants (rivaroxaban, apixaban) alone and in combination with cobicistat or darunavir/cobicistat in healthy volunteers.	Days 1, 7 and 13 at the following times: Arm A (Rivaroxaban): times 0 (predose), 1, 2, 3, 4, 6, 8, 10 and 24 hours post-dose. Arm B (Apixaban): times 0 (predose), 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose.

Collaborators and Investigators

• Sponsor: National Institutes of Health Clinical Center (CC)
• Investigators: Principal Investigator: Colleen M Hadigan, M.D., National Institutes of Health Clinical Center (CC)

Publications and helpful links

General Publications

• Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013 Sep;76(3):455-66. doi: 10.1111/bcp.12075.
• Kumar P, Gordon LA, Brooks KM, George JM, Kellogg A, McManus M, Alfaro RM, Nghiem K, Lozier J, Hadigan C, Penzak SR. Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran. Antimicrob Agents Chemother. 2017 Oct 24;61(11):e01201-17. doi: 10.1128/AAC.01201-17. Print 2017 Nov.
• Frost C, Nepal S, Wang J, Schuster A, Byon W, Boyd RA, Yu Z, Shenker A, Barrett YC, Mosqueda-Garcia R, Lacreta F. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol. 2013 Nov;76(5):776-86. doi: 10.1111/bcp.12106.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): June 4, 2019
• Primary Completion (Actual): December 10, 2022
• Study Completion (Actual): December 10, 2022

Study Registration Dates

• First Submitted: March 5, 2019
• First Submitted That Met QC Criteria: March 5, 2019
• First Posted (Actual): March 6, 2019

Study Record Updates

• Last Update Posted (Estimated): December 1, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Thrombosis; Bleeding; Antiretroviral Therapy; Human Immunodeficiency Disease; Drug-Drug Interactions
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; HIV Protease Inhibitors; Viral Protease Inhibitors; Cobicistat; Rivaroxaban; Darunavir; Cobicistat mixture with darunavir
• Other Study ID Numbers: 190063; 19-CC-0063

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not reported or shared. The study team are the only individuals who have access to individual participant data. All data will be analyzed and reported in aggregate.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No