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

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.

- 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 18-65 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.