Clinical trial NCT00000877: 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
Official title: Steady-State Pharmacokinetic Interaction Study of Indinavir and Rifabutin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: Rifabutin
Drug Therapy, Combination
HIV Protease Inhibitors
Indinavir
HIV Seronegativity
Anti-HIV Agents
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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. \[AS PER AMENDMENT 8/8/97: Patients treated on Arm A are randomized, following Period IA therapy, to Period IIA or IIIA therapy for 14 days, then are crossed over to the alternate regimen for 14 days.\] \[AS PER AMENDMENT 4/17/98: After completion of therapy on Arm A or B, patients continue therapy with indinavir alone for 7 days.\] \[AS PER AMENDMENT 11/16/98: The final 7 days of indinavir dosing has been eliminated for patients on Arm A. Also per this amendment, to ensure compliance, Arm A patients' rifabutin supply will be dispensed in containers fitted with an electronic monitoring cap device.\]

Eligibility criteria: Inclusion Criteria

You may be eligible for this study if you:

* Are HIV-positive or HIV-negative.
* Agree to practice abstinence or to use birth control during the study.

Exclusion Criteria

You will not be eligible for this study if you:

* Have an active opportunistic (HIV-associated) disease or other disease requiring medication within 14 days of study entry.
* Have a history of illness that might put you at risk if given either of the study drugs.
* Have had any severe allergies to any substance in the past.
* Have a history of kidney stones.
* Have a medical condition, or problems with use of alcohol or drugs, which would keep you from completing the study.
* Have had tuberculosis and have never been treated for it.
* Are pregnant or breast-feeding.
* Are taking certain medications.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Univ of Southern California / LA County USC Med Ctr
state: California
city: Los Angeles
country: United States
facility: Univ of Southern California / LA County USC Med Cntr
state: California
city: Denver
country: United States
facility: Univ of Colorado Health Sciences Ctr
state: Colorado
city: Miami
country: United States
facility: Univ of Miami School of Medicine
state: Florida
city: Indianapolis
country: United States
facility: Indiana Univ Hosp
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins Hosp
state: Maryland
city: New York
country: United States
facility: Bellevue Hosp / New York Univ Med Ctr
state: New York
city: New York
country: United States
facility: Cornell Univ Med Ctr
state: New York
Study officials:
name: Charles Flexner
role: STUDY_CHAIR
name: Constance Benson
role: STUDY_CHAIR
name: Judith Currier
role: STUDY_CHAIR
References:
citation: Hamzeh FM, Benson C, Gerber J, Currier J, McCrea J, Deutsch P, Ruan P, Wu H, Lee J, Flexner C; AIDS Clinical Trials Group 365 Study Team. Steady-state pharmacokinetic interaction of modified-dose indinavir and rifabutin. Clin Pharmacol Ther. 2003 Mar;73(3):159-69. doi: 10.1067/mcp.2003.3.
citation: Hennig S, Svensson EM, Niebecker R, Fourie PB, Weiner MH, Bonora S, Peloquin CA, Gallicano K, Flexner C, Pym A, Vis P, Olliaro PL, McIlleron H, Karlsson MO. Population pharmacokinetic drug-drug interaction pooled analysis of existing data for rifabutin and HIV PIs. J Antimicrob Chemother. 2016 May;71(5):1330-40. doi: 10.1093/jac/dkv470. Epub 2016 Jan 31.