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

  • STATUS
    Recruiting
  • End date
    Aug 30, 2021
  • participants needed
    75
  • sponsor
    National Institutes of Health Clinical Center (CC)
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Updated on 26 January 2021
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body mass index
fasting
blood test

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):

<TAB>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.

<TAB>Dose of rivaroxaban or apixaban

<TAB>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.

<TAB>Dose of rivaroxaban or apixaban

<TAB>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

Description

Rivaroxaban and apixaban are direct oral anticoagulants (DOACs) 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 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 and apixaban. Rivaroxaban and apixaban are both metabolized by cytochrome P450 isozyme (CYP) 3A4 and their 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 and apixaban 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 DRV/COBI on the PK and PD of single oral doses of rivaroxaban and apixaban.

Details
Condition Diet and Nutrition, Chronic Diarrhea, Skin Wounds, Chronic Shoulder Pain, Vaginal Atrophy, Adverse Effects, Drugs, Injection Port, Breast Cancer - HER2 Positive, Anal Dysplasia, Primary Immunodeficiency, Pediatric Health, Near-Sighted Corrective Surgery, Healthy Volunteers, Peripheral Arterial Occlusive Disease, Brain Function, Recurrent Respiratory Papillomatosis, Razor Bumps (Pseudofolliculitis Barbae), Metastatic Triple-Negative Breast Cancer
Treatment ELIQUIS (APIXABAN), Tybost (Cobicistat), Prezcobix (Darunavir/Cobicistat), Xarelto (Rivaroxaban)
Clinical Study IdentifierNCT03864406
SponsorNational Institutes of Health Clinical Center (CC)
Last Modified on26 January 2021

Eligibility

 Yes No Not Sure

Inclusion Criteria

Is your age between 18 yrs and 65 yrs?
Gender: Male or Female
Do you have any of these conditions: or Pediatric Health or Brain Function or Metastatic Triple-Negative Breast Cancer or Recurrent Respiratory Papillomatosis or Chronic Shoulder Pain or...?
Do you have any of these conditions: or Near-Sighted Corrective Surgery or Healthy Volunteers or Chronic Diarrhea or Adverse Effects, Drugs or Peripheral Arterial Occlusive Disease or Br...?
Do you have any of these conditions: or Chronic Diarrhea or Anal Dysplasia or Vaginal Atrophy or Adverse Effects, Drugs or Razor Bumps (Pseudofolliculitis Barbae) or Chronic Shoulder Pai...?
Do you have any of these conditions: or Metastatic Triple-Negative Breast Cancer or Injection Port or Recurrent Respiratory Papillomatosis or Chronic Diarrhea or Primary Immunodeficiency...?
A subject will be considered eligible for this study only if all of the
following criteria are met
Adults between the ages of 18-65 years
Body Mass Index (BMI) between 18-30 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, PLT > 150,000/microL, hemoglobin (Hgb) greater than or equal to 12 g/dL, aPTT less than or equal to ULN, PTT less than or equal to ULN, 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
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