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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
37
rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Johns Hopkins University
Baltimore, Maryland, United States
Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial
Number of Participants with Grade 2 or higher adverse events over 26 days
Time frame: 26 days
Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose)
To determine and compare the steady-state pharmacokinetics and dose linearity of escalating daily doses of rifapentine in dose cohorts of 5 mg/kg, 10 mg/kg, 15 mg/kg and 20 mg/kg in healthy volunteers after a single dose (Day 2) or multiple doses (Day 15)
Time frame: days: 2, 15
Midazolam, AUC Over 12 Hours Post-dose
To compare and describe, the pharmacokinetics of single-dose midazolam alone (Day 1) versus midazolam co-administered with either steady-state rifapentine at multiple daily doses (5, 10, 15, and 20 mg/kg) or rifampin at 10 mg/kg daily (Day 15)
Time frame: days: 1, 15
Transporter Genes
To determine the effects of polymorphisms of transporter genes on rifampin and rifapentine PK parameters
Time frame: day 3
Rifapentine Concentrations From Dried Blood Spots
To develop methods for determination of rifapentine concentrations from dried blood spots on sampling paper
Time frame: days 2, 3, 7, 10, 15, 16, 17, 18
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rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
rifapentine - tablet, 2.5 mg/kg lower than previously tolerated dose cohort, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15