Effects of Four Different Meal Types on the Population Pharmacokinetics of Single-Dose Rifapentine in Healthy Male Volunteers

Rifapentine and its primary metabolite, 25-desacetyl rifapentine, are active against mycobacterium tuberculosis. The objectives of this study were to describe the population pharmacokinetics of rifapentine and 25-desacetyl rifapentine in fasting and fed states. Thirty-five male healthy volunteers were enrolled in an open-label, randomized, sequential, five-way crossover study. Participants received a single 900-mg dose of rifapentine after meals with high fat (meal A), bulk and low fat (meal B), bulk and high fat (meal C), high fluid and low fat (meal D), or 200 ml of water (meal E). Venous blood samples were collected over 72 h after each rifapentine dose, and plasma was analyzed for rifapentine and 25-desacetyl rifapentine using high-performance liquid chromatography. Pharmacokinetic data were analyzed by nonlinear mixed-effect modeling using NONMEM. Compared with the fasting state, meal A had the greatest effect on rifapentine oral bioavailability, increasing it by 86%. Meals B, C, and D resulted in 33%, 46%, and 49% increases in rifapentine oral bioavailability, respectively. Similar trends were observed for 25-desacetyl rifapentine. As meal behavior has a substantial impact on rifapentine exposure, it should be considered in the evaluation of optimal dosing approaches.Rifapentine (RFP), a cyclopentyl rifamycin, is an orally administered drug registered by the Food and Drug Administration (FDA) for the treatment of pulmonary tuberculosis (TB). It exerts its antibacterial activity through inhibition of DNA-dependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis (32). RFP has a microbiologically active metabolite, 25-desacetyl rifapentine (25-DRFP) (10). RFP has a long half-life (5, 17) and superior in vitro potency against M. tuberculosis in comparison with rifampin and rifabutin (10), making it an attractive candidate for shortening and simplifying antitubercular therapy.Currently, RFP is dosed at 600 mg either once weekly or twice weekly in human immunodeficiency virus (HIV)-negative patients with noncavitary TB (2). There is concern that the development of acquired rifamycin monoresistance (ARR), treatment failure, and relapse may be associated with intermittent dosing (4, 20), insufficient companion drug exposure (33), or low rifamycin concentrations (9, 21). RFP''s sterilizing effect has been shown to be dose dependent in murine studies which suggest that daily doses of RFP may reduce treatment duration to just 3 months (25, 26, 37), and higher doses of RFP are associated with improved early bactericidal activity in humans (29). Clinical trials are currently evaluating new antituberculosis regimens containing higher doses of RFP used intermittently or daily doses of RFP. Concomitant food has a marked effect on RFP absorption (6). The effect of food on systemic RFP exposure may therefore impact treatment activity and safety. The aim of this study was to investigate the effect of meals differing in fat and bulk content on the rate and extent of RFP absorption and 25-DRFP disposition. The study was designed to include meals comprising largely maize, a staple cereal in many parts of Africa and South America, and a light meal (i.e., a reconstituted powdered chicken soup). The study was conducted in 1999 shortly after the release of results from studies evaluating intermittent 600-mg doses of rifapentine, which displayed unacceptably high relapse rates in patients with lung cavities or immune suppression. It was therefore anticipated that future studies would evaluate higher doses of the drug.