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

NCT03864406 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 19006319-CC-0063
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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

Conditions

Healthy Volunteers

Keywords

Antiretroviral Therapy; Human Immunodeficiency Disease; Drug-Drug Interactions; Thrombosis; Bleeding

Outcome Measures

Primary Outcomes (8)

• 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

Study Arms (1)

Pharmacokinetic study in healthy volunteers

EXPERIMENTAL

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; Drug: Darunavir/Cobicistat; Drug: Rivaroxaban

Interventions

Cobicistat DRUG

Each tablet of Tybost contains 150 mg of cobicistat.

Also known as: Tybost

Pharmacokinetic study in healthy volunteers

Darunavir/Cobicistat DRUG

Each tablet of Prezcobix contains 800 mg of darunavir and 150 mg of cobicistat.

Also known as: Prezcobix

Pharmacokinetic study in healthy volunteers

Rivaroxaban DRUG

Each tablet of Xarelto contains 10 mg of rivaroxaban.

Also known as: Xarelto

Pharmacokinetic study in healthy volunteers

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institutes of Health Clinical Center (CC): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• 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.

  PMID: 23305158 BACKGROUND

• 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.

  PMID: 28848011 BACKGROUND

• 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.

  PMID: 23451769 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Thrombosis; Hemorrhage

Interventions

Cobicistat; cobicistat mixture with darunavir; Rivaroxaban

Condition Hierarchy (Ancestors)

Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiophenes; Morpholines; Oxazines

Results Point of Contact

• Title: Hadigan, Colleen
• Organization: Clinical Center

hadiganc@niaid.nih.gov

+1 301 594 5754

Study Officials

• Colleen M Hadigan, M.D.

  National Institutes of Health Clinical Center (CC)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 5, 2019
• First Posted: March 6, 2019
• Study Start: June 4, 2019
• Primary Completion: December 10, 2022
• Study Completion: December 10, 2022
• Last Updated: December 1, 2023
• Results First Posted: December 1, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)