Clinical trial NCT01162486
Conditions: Tuberculosis Tuberculosis, Pulmonary
Keywords: Anti-infective agents Anti-bacterial agents Rifampin Rifapentine Midazolam Molecular mechanisms of pharmacological action Antitubercular agents Pharmacologic actions
Sponsor: Johns Hopkins University
Start date: 2010-04-01; Completion date: 2011-03-01
Enrollment: 37 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this study is to evaluate (1) the safety and tolerability of escalating doses of rifapentine (RPT) administered daily by oral; (2) the effect of increasing doses of RPT on cytochrome P450 isoform 3A (CYP3A) enzyme metabolizing activity, using single-dose midazolam (MDZ); and (3) the effect of increasing doses of RPT on autoinduction of RPT metabolism.

Detailed description:
On day 1, volunteers will receive a single dose of MDZ dosed at 15 mg delivered orally, and a 24-hour PK analysis of MDZ and its metabolite, 1-OH-midazolam (1-OH-MDZ) will be performed. RPT (or RIF) will be given as a single daily dose (5, 10, 15, or 20 mg/kg, depending on the dose cohort) on days 2-15 (14 doses). A 24-hour PK analysis of RPT (or RIF) and its 25-deacetyl metabolite (25-des-RPT) will be performed after the first dose (day 2). On day 15, volunteers receive a second single dose of MDZ. A 72-hour RPT (or RIF) and 24-hour MDZ (and 1-OH-MDZ) PK analysis will be performed after the second dose of MDZ beginning on day 15. The PK sampling will occur both on an in-patient basis in the General Clinical Research Center (GCRC) and on an out-patient basis in the study clinic. Volunteers will undergo assessments for adverse events (AEs) several times throughout the study.

Each dose cohort will contain 6 subjects. RPT dosing will begin at 5 mg/kg (6 volunteers) and increase by 5 mg/kg increments (6 volunteers each at 10, 15, and 20 mg/kg) to a maximum dose of 20 mg/kg unless dose-limiting toxicities (DLT) are seen in two or more patients within a dose cohort, in which case a dose that is 2.5 mg/kg lower than the previous dose will be enrolled to determine the maximal tolerated dose (MTD). In addition, one cohort of 6 subjects will receive RIF at 10 mg/kg daily, rather than RPT, as a comparator arm.

Arms: arm 1: Rifampin + midazolam arm 2: RPT Cohort 1 - 5 mg/kg arm 3: RPT Cohort 2 - 10 mg/kg arm 4: RPT Cohort 3 - 15 mg/kg arm 5: RPT Cohort 4 - 20 mg/kg arm 6: RPT Cohort 5 - Maximal tolerated dose, if dose limiting toxicities are observed
Interventions: intervention 1: Rifampin & midazolam intervention 2: rifapentine & midazolam intervention 3: rifapentine & midazolam intervention 4: rifapentine & midazolam intervention 5: rifapentine and midazolam intervention 6: rifapentine and midazolam
Intervention descriptions: intervention 1: rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 intervention 2: rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 intervention 3: rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 intervention 4: rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 intervention 5: rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 intervention 6: rifapentine - tablet, 2.5 mg/kg lower than previously tolerated dose cohort, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

Protocol documents: