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.

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