Pharmacokinetics, Safety and Tolerability of Escalating Rifapentine Doses in Healthy Volunteers
Condition: Tuberculosis; Tuberculosis, Pulmonary
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Rifampin & midazolam; rifapentine & midazolam; rifapentine & midazolam; rifapentine & midazolam; rifapentine and midazolam; rifapentine and midazolam
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 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; 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
Intervention MeSH terms: Rifampin; Rifapentine; Midazolam
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Anti-infective agents; Anti-bacterial agents; Rifampin; Rifapentine; Midazolam; Molecular mechanisms of pharmacological action; Antitubercular agents; Pharmacologic actions