NCT01162486

Pharmacokinetics, Safety and Tolerability of Escalating Rifapentine Doses in Healthy Volunteers

Phase I Dose Escalation Study of the Pharmacokinetics, Safety and Tolerability of Rifapentine and the Effects of Increasing Doses of Rifapentine on Induction of Metabolizing Enzymes in Healthy Volunteers

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 37 (actual)
• Sponsor: Johns Hopkins University · Academic / Other
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Accepted

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.

Conditions

• Tuberculosis
• Tuberculosis, Pulmonary

Interventions

Type	Name	Description
DRUG	Rifampin & midazolam	rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
DRUG	rifapentine & midazolam	rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
DRUG	rifapentine & midazolam	rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
DRUG	rifapentine & midazolam	rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
DRUG	rifapentine and midazolam	rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
DRUG	rifapentine and midazolam	rifapentine - tablet, 2.5 mg/kg lower than previously tolerated dose cohort, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

Timeline

• Start date: 2010-04-01
• Primary completion: 2011-02-01
• Completion: 2011-03-01
• First posted: 2010-07-14
• Last updated: 2019-05-07
• Results posted: 2019-05-07

Locations

1 site across 1 country: United States