Impact of Once-Weekly Rifapentine and Isoniazid on the Steady State Pharmacokinetics of Dolutegravir and Darunavir Boosted With Cobicistat in Healthy Volunteers
Condition: HIV Infected Population With Latent Tuberculosis
MeSH terms: Tuberculosis; Latent Tuberculosis
Study type: Interventional
Phase: Phase 1

Summary: 
      People with human immunodeficiency virus (HIV) often take several medicines to control HIV.
      Dolutegravir and darunavir boosted with cobicistat are HIV medicines that people may take.
      They may also need to take medicines for an infection called latent tuberculosis (TB).
      Researchers think a once-weekly treatment for latent TB would be easier for people with HIV
      to take. This once weekly treatment consists of two drugs: rifapentine and isoniazid.
      However, they need to see how TB drugs and HIV drugs interact.

      Objective:

      To learn how anti-HIV and anti-TB drugs affect each other so that people taking these drugs
      together can be treated safely.

      Eligibility:

      Healthy adults ages 18 65.

      Design:

      Participants will be screened with a medical history and physical exam. They will have vital
      signs taken and give a blood sample. Women will have a pregnancy test.

      Participants cannot take any other medicines during the study, including vitamins. Only
      occasional, infrequent use of acetaminophen (Tylenol , max 2000 mg/day), ibuprofen (Motrin or
      Advil ), naproxen (Aleve ), loperamide (Imodium ), and/or antihistamines (such as Benadryl ,
      Zyrtec , Claritin , etc.) will be allowed.

      Participants will be assigned to one of three groups. Each group will take a different study
      drug, once or twice a day, for 19 23 days. At the baseline study visit, they will get a
      supply of the study drug tablets and instructions for taking them. Participants will keep a
      medicine diary to serve as a memory aid for taking medicine and reporting any side effects
      that they may experience.

      Participants will have 8 or 9 study visits over about 40 days. The number of visits depends
      on which group the person is assigned to. All visits will take place at the NIH Clinical
      Center. Participants will fast before study visits.

      The baseline visit will last about 2 3 hours. There will be 3-4 long visits that will last
      for about 12 hours. The other 4-5 visits will last about 1 hour.

      During all study visits, screening procedures will be repeated. During long visits, an
      intravenous (IV) line will be inserted into an arm vein with a needle. It will be used to
      take blood.
    

Detailed description: 
      Rifapentine (RPT) is a long-acting rifamycin that can be used weekly with isoniazid (INH) as
      a first-line regimen in the treatment of latent tuberculosis infection (LTBI). Although this
      regimen offers several potential benefits, the use of weekly RPT plus INH is not currently
      recommended in adults infected with human immunodeficiency virus (HIV) on antiretroviral
      therapy (ART) due to limited evidence on drug interactions with antiretrovirals
      (ARVs).1Darunavir boosted with cobicistat (DRV/c) comprises part of alternative treatment
      regimens recommended for the treatment of HIV.2However, drug interactions between these ARV
      agents and RPT are of concern. Thus, the purpose of this study is to determine the effects of
      concomitant RPT and INH administration on the steady state PK of DRV/c.

      This is an open-label, fixed sequence, intrasubject drug-drug interaction study designed to
      evaluate the steady state PK of DRV/c with coadministration of once weekly RPT and INH given
      at doses used to treat LTBI. Arm B will be comprised of two phases: (1) DRV/c once daily
      alone (days 1-4) and (2) DRV/c once daily + (RPT and INH) once weekly (days 5-19).
      Participants in Arm B will undergo periodic serial ARV PK blood draws on days 4, 14, and 19.

      DRV/c PK parameters will be determined using non-compartmental methods. Cobicistat levels
      will only be assessed if DRV concentrations are significantly decreased. The following PK
      parameters will be compared between phases: area under the curve over the dosing interval,
      maximum plasma concentration, time to maximum plasma concentration, terminal half-life,
      apparent oral clearance, and minimum plasma concentration. Adverse events will be graded and
      recorded.
    

Intervention name(s): rifapentene (RPT); darunavir/cobicistat (DRV/c); Isoniazid (INH); Pyridoxine
Intervention type(s): Drug; Drug; Drug; Dietary Supplement
Intervention description(s): RPT is a long-acting rifamycin used in combination with INH in the treatment of LTBI.; DRV is a protease inhibitor (PI) indicated in the treatment of HIV infection.33 DRV requires coadministration with RTV (100 mg once or twice daily) or COBI (150 mg daily), the latter of which has been coformulated into a fixed-dose tablet with DRV (DRV/c 800/150 mg).; INH is an antimycobacterial agent that can be used alone or in combination with RPT for the treatment of LTBI. Given with Pyridoxine (vitamin B6)
Intervention MeSH terms: Pyridoxine; Isoniazid; Darunavir; Cobicistat; Cobicistat mixture with darunavir
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Fixed Sequence; Intrasubject Drug-Drug Interaction; Open-Label