Impact of Steady State Cobicistat and Darunavir/Cobicistat on the Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants (Rivaroxaban, Apixaban) in Health Volunteers
Condition: Healthy Volunteers
Intervention: Cobicistat; Darunavir/Cobicistat; Rivaroxaban
Intervention description: Each tablet of Tybost contains 150 mg of cobicistat.; Each tablet of Prezcobix contains 800 mg of darunavir and 150 mg of cobicistat.; Each tablet of Xarelto contains 10 mg of rivaroxaban.
Intervention MeSH terms: Darunavir; Cobicistat; Cobicistat mixture with darunavir; Rivaroxaban
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Antiretroviral Therapy; Human Immunodeficiency Disease; Drug-Drug Interactions; Thrombosis; Bleeding

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
    

Eligibility criteria:

        -  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.