Pharmacokinetics, Safety and Tolerability of Escalating Rifapentine Doses in Healthy Volunteers
Condition: Tuberculosis; Tuberculosis, Pulmonary
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Intervention: Rifampin & midazolam; rifapentine & midazolam; rifapentine & midazolam; rifapentine & midazolam; rifapentine and midazolam; rifapentine and midazolam
Intervention description: 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
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 37.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Anti-infective agents; Anti-bacterial agents; Rifampin; Rifapentine; Midazolam; Molecular mechanisms of pharmacological action; Antitubercular agents; Pharmacologic actions

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Ability and willingness to provide written informed consent.

          2. Age greater than or equal to 18 years, and less than or equal to 65 years.

          3. Weight of 50-100 kg for enrollment into the RPT cohorts

          4. Weight of 50-80 kg for enrollment into the RIF cohort

          5. Within 28 or fewer days prior to enrollment, a complete blood count with differential,
             comprehensive serum chemistry profile, HIV antibody test, and Hepatitis C antibody
             test will be performed, with the following laboratory values:

               1. Serum amino aspartate transferase (AST) less than the upper limit of normal

               2. Total bilirubin level less than the upper limit of normal

               3. Serum creatinine <1.5 mg/dL

               4. Hemoglobin greater than 12.0 for men, greater than 11.0 for women

               5. Platelet count greater than or equal to 125,000 /cu mm

               6. Absolute neutrophil count greater than or equal to 1250 /cu mm

               7. Serum albumin greater than 3.5 g/dL

               8. HIV antibody test negative

               9. Hepatitis C antibody negative

          6. For women of childbearing potential, a negative serum bHCG pregnancy test, performed
             at screening.

          7. During the study and for 14 days after the last dose of study medication, women of
             childbearing potential must agree to practice barrier contraception for the duration
             of the study.

        Exclusion Criteria:

          1. Pregnant or breastfeeding

          2. Known intolerance of or allergy to rifamycins

          3. Allergy to benzodiazepines

          4. Use of rifamycin antibiotics in the 30 days prior to enrollment

          5. Inability to take oral medications

          6. Renal, hepatic, cardiac (except benign heart murmur), or endocrine disorder; or
             malignancy; or immunocompromise.

          7. History of any acute or chronic illness that requires current medical therapy.

          8. Prior gastrointestinal surgery involving stomach, biliary system, pancreas, or small
             intestine.

          9. Any medical condition that, in the opinion of the investigator, would interfere with
             the subject's ability to participate in the protocol.

         10. Any illicit drug use within the preceding 2 months. Subjects must agree to abstain
             from alcohol and illicit drug use during the study. Smokers must agree to abstain from
             cigarettes or to smoke fewer than 5 cigarettes per day.

         11. Current use of any prescription medication(s), including oral contraceptives.

         12. Planned use, during the study from Day 0 through the last PK blood draw, of any of the
             following: prescription medication(s), herbal supplement(s), vitamin(s), mineral
             supplement(s), over-the-counter medication(s), or grapefruit juice. Subjects must
             agree to abstain from grapefruit juice during the study.

         13. Participation in any other investigational drug study within 30 days prior to study
             entry and during study.

         14. Inability to participate in pharmacokinetic visits