Study of How Indinavir (an Anti-HIV Drug) and Rifabutin (a Drug Used to Treat MAC, an HIV-Associated Disease) Interact in HIV-Positive and HIV-Negative Adults
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to evaluate the safety of giving indinavir and rifabutin at the
      same time (simultaneously) vs 4 hours apart (staggered) to HIV-positive and HIV-negative
      adults.

      It is important to determine which medications for HIV-associated diseases, such as
      Mycobacterium avium complex (MAC) disease, can be given safely and effectively with anti-HIV
      drugs. Indinavir and rifabutin have been given simultaneously in the past with good results.
      This study seeks to examine if staggering the doses will make the 2 drugs more effective.
      HIV-negative volunteers are used in this study to examine the effect of rifabutin on
      indinavir and the effect of staggered rifabutin doses. The effect of rifabutin on the drug
      activity of indinavir is evaluated in HIV-positive patients.
    

Detailed description: 
      Currently, rifabutin is the only rifamycin that can be administered with indinavir. ACTG 365
      is the first formal study of the pharmacokinetics of this dosing combination regimen in HIV
      seropositive patients. It is hypothesized that staggered administration of rifabutin and
      indinavir might minimize their pharmacokinetic interaction. If the intestinal tract plays a
      significant role in the presystemic clearance of rifabutin, the inhibitory activity of
      indinavir on rifabutin could depend on either luminal concentrations of indinavir, systematic
      concentrations of indinavir, or both. If luminal concentrations are important, then the
      interaction between these 2 drugs will be maximal when administered simultaneously, and
      minimal when their oral administration is staggered. Finally, since indinavir has a half-life
      of 1.8 hours, its effects on rifabutin's systematic clearance may be much less when
      administration of these drugs is staggered by 4 hours as compared with simultaneous
      administration with rifabutin. If the interaction on rifabutin is minimized, then the
      rifabutin levels may be suboptimal for treatment of tuberculosis in patients who are not
      administered the 2 drugs simultaneously. It is, therefore, important to define the magnitude
      of the effect of staggered vs simultaneous drug administration in order to clarify dose and
      regimen recommendations in HIV-infected patients with tuberculosis who also require protease
      inhibitor therapy.

      Study Arm A is a multiple-dose, 3-period, sequential study in 18 evaluable HIV-infected
      indinavir-naive male and female volunteers [AS PER AMENDMENT 11/16/98: Arm A will be assessed
      in 18 evaluable HIV-seronegative patients]. Patients receive 3 different treatments
      consisting of 14 days of administration: rifabutin alone (Period IA); indinavir plus
      rifabutin (Period IIA); and indinavir plus rifabutin (Period IIIA). Study Arm B is a
      multiple-dose, 2-period, sequential study in 10 evaluable HIV-infected male and female
      volunteers. Patients receive 2 different treatments, each consisting of 14 days of
      administration; indinavir alone (Period IB); and indinavir plus rifabutin (Period IIB).
      Patients on both arms take each dose of their study medications with water. [AS PER AMENDMENT
      8/8/97: Patients treated on Arm A are randomized, following Period IA therapy, to Period IIA
      or IIIA therapy for 14 days, then are crossed over to the alternate regimen for 14 days.] [AS
      PER AMENDMENT 4/17/98: After completion of therapy on Arm A or B, patients continue therapy
      with indinavir alone for 7 days.] [AS PER AMENDMENT 11/16/98: The final 7 days of indinavir
      dosing has been eliminated for patients on Arm A. Also per this amendment, to ensure
      compliance, Arm A patients' rifabutin supply will be dispensed in containers fitted with an
      electronic monitoring cap device.]
    

Intervention name(s): Indinavir sulfate; Rifabutin
Intervention type(s): Drug; Drug
Intervention MeSH terms: Indinavir; Rifabutin
Intervention model: Parallel Assignment
Primary purpose: Treatment
Keywords: Rifabutin; Drug Therapy, Combination; HIV Protease Inhibitors; Indinavir; HIV Seronegativity; Anti-HIV Agents