The Interaction of Two HIV Medications With Blood Clot Medications in Healthy Volunteers
Condition: HIV
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - People who have the human immunodeficiency virus (HIV) often take several medications to
      control their disease. They may also need to take medicine to prevent blood clots. Taking
      both kinds of medicine together can cause bleeding or other problems. But this might not
      happen if the medications are taken at different times. Researchers will study two particular
      HIV drugs (ritonavir and cobicistat) and how they interact with blood clot medications.

      Objectives:

      -To understand how HIV medicine and blood clot medicine interact, so doctors can choose what
      to prescribe for people who take both.

      Eligibility:

      - Healthy adults between 18 and 70 years old who are not on any medications.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood samples
           will be collected. Urine samples will be collected from participants who might become
           pregnant.

        -  Participants will visit the National Institutes of Health 7 times after the screening
           visit. Three visits will last about 12 hours. The other 4 will last about 1 hour.

        -  Participants will take a daily dose of either study medication for 22 days. They will
           keep a diary of medicine they take and any side effects.

        -  Treatment will be monitored with blood tests over about 2 months.

        -  When the study of one drug is completed, the next drug study will begin with a different
           group of participants.
    

Detailed description: 
      Advances in antiretroviral (ARV) pharmacotherapy have translated to increased longevity and
      improved quality of life in people living with HIV; hence, elderly individuals comprise an
      increasing proportion of today s HIV population. Moreover, HIV infection itself has become
      recognized as a condition characterized by a hypercoaguable state and premature immunologic
      aging. Potential interactions between ARVs and anticoagulant medications are of particular
      concern considering that many elderly, and even non-elderly HIV patients will require
      short-term or chronic anticoagulation to prevent and/or treat systemic embolism. Dabigatran,
      administered as dabigatran etexilate, is an oral irreversible, competitive direct thrombin
      inhibitor, which has been shown to be superior to warfarin, and non-inferior to enoxaparin,
      in preventing thromboembolism in patients with atrial fibrillation and undergoing orthopedic
      surgery, respectively.

      While dabigatran itself is not a substrate of Permeability-glycoprotein (P-gp), its
      inactivepro-drug, dabigatran etexilate, is a substrate of P-gp. Co-administration of
      dabigatran etexilate with P-gp modulators has resulted in significant changes in dabigatran
      exposure. The pharmacokinetic enhancers, ritonavir and cobicistat, as inhibitors of P-gp, are
      expected to increase plasma concentrations of dabigatran; however, neither agent has been
      studied in combination with dabigatran etexilate, to date. Hence, the purpose of this study
      is to determine whether the separate co-administration of ritonavir or cobicistat with
      dabigatran etexilate increases the systemic exposure of dabigatran in healthy volunteers, and
      if so, whether adjusting the administration times of these medications can circumvent this
      interaction.

      In this open-label study, 32 healthy volunteers will be assigned to 1 of 2 groups. Group A
      will consist of 16 subjects who will take 22 days of ritonavir; Group B will consist of 16
      subjects who will take 22 days of cobicistat. All subjects will receive 3 separated single
      doses of dabigatran etexilate. Pharmacokinetic (PK) and pharmacodynamics (PD) sampling for
      dabigatran will occur on Days 0 1, Day 19 1 20, and Day 26 1 27.

      The PD effects of dabigatran will be characterized via ecarin clotting time (ECT)
      measurements. Dabigatran PK/PD parameters will be determined using non-compartmental methods
      with the WinNonlin professional computer program (version 5.2; Pharsight Corporation,
      Mountain View, CA). The following PK/PD parameters will be compared between the groups: area
      under the curve from 0 to 24 hours (AUC0-24), maximum total dabigatran plasma concentration
      (Cmax), area under the curve from 0 to infinity hours (AUC0- ), time to maximum plasma
      concentration (tmax), terminal half-life (T (Omega)), apparent oral clearance (CL/F), area
      under the effect curve from 0 to 24 hours (AUEC0-24), and the maximum effect ratio over
      baseline (ERmax).
    

Intervention name(s): Ritonavir; Cobicistat
Intervention type(s): Drug; Drug
Intervention description(s): Impact on dabigatran PK/PD; Impact on dabigatran PK/PD
Intervention MeSH terms: Ritonavir; Cobicistat
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Dabigatran Etexilate; Ritonavir; Cobicistat; P-Glycoprotein