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.
Division of Clinical Pharmacology, K-45 Old Main Building, Groote Schuur Hospital, Observatory 7925, Cape Town, South Africa.
Simbarashe P
SP
Zvada
Jan-Stefan
JS
Van Der Walt
Peter J
PJ
Smith
P Bernard
PB
Fourie
Giorgio
G
Roscigno
Denis
D
Mitchison
Ulrika S H
US
Simonsson
Helen M
HM
McIlleron
D000284:Administration, Oral; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004041:Dietary Fats / Q000494:pharmacology*; D005215:Fasting / Q000378:metabolism*; D006801:Humans; D008297:Male; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016896:Treatment Outcome; D055815:Young Adult
D000904:Antibiotics, Antitubercular; D004041:Dietary Fats; D012293:Rifampin; C018421:rifapentine