Clinical trial NCT03864406: Impact of Steady State Cobicistat and Darunavir/Cobicistat on the Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants (Rivaroxaban, Apixaban) in Health Volunteers
Official title: Impact of Steady State Cobicistat and Darunavir/Cobicistat on the Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants (Rivaroxaban, Apixaban) in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Antiretroviral Therapy
Human Immunodeficiency Disease
Drug-Drug Interactions
Thrombosis
Bleeding
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2019-03-06
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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

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.

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.

Primary outcomes:
measure: Area Under the Concentration Versus Time Curve (AUC0-∞) for Rivaroxaban
timeFrame: Total drug exposure at time point zero to infinity on days 1, 7, & 13
measure: Area Under the Concentration Versus Time Curve (AUC0-24hr) for Rivaroxaban
timeFrame: 0 to 24 hours postdose on days 1, 7, and 13
measure: Maximum Total Plasma Concentration (Cmax) for Rivaroxaban
timeFrame: Up to 24 hours postdose on days 1, 7, and 13
measure: Time to Maximum Plasma Concentration (Tmax) for Rivaroxaban
timeFrame: Up to 24 hours postdose on days 1, 7, and 13
measure: Terminal Elimination Half-life (t½) for Rivaroxaban
timeFrame: Up to 24 hours postdose on days 1, 7, and 13
measure: Apparent Oral Clearance (CL/F) for Rivaroxaban
timeFrame: Up to 24 hours postdose on days 1, 7, and 13
measure: Apparent Volume of Distribution (V/F) for Rivaroxaban
timeFrame: Up to 24 hours postdose on days 1, 7, and 13
measure: Minimum Total Plasma Concentration (Cmin) for Rivaroxaban
timeFrame: Up to 24 hours postdose on days 1, 7, and 13
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institutes of Health Clinical Center (CC)
name: Colleen M Hadigan, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.