Effect of Various Meals on the Population Pharmacokinetics of Rifapentine
Simbarashe P. Zvada (1), Jan-Stefan Van Der Walt (1,2), Peter J. Smith (1), P Bernard Fourie (3), Giorgio Roscigno (4), Denis Mitchison (5), Ulrika S.H. Simonsson (2), Helen M. McIlleron (1)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; (2) Department of Pharmaceutical Biosciences, Uppsala University, Sweden; (3) Medicine in Need South Africa, Pretoria, South Africa; (4) Foundation for Innovative New Diagnostics, Geneva, Switzerland; (5) St. George’s Hospital Medical School, London, United Kingdom
Objectives: 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.
Methods: 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) content, or with 200 mLs of water (meal E). Venous blood samples were collected over 72 h after each RFP dose. Plasma concentrations of rifapentine and 25- desacetyl rifapentine were determined using a validated high-performance liquid chromatography (HPLC) method. Pharmacokinetic data for rifapentine and 25-desacetyl rifapentine were analysed in an integrated model using nonlinear mixed-effect modeling in NONMEM IV version 2 (FOCE INTER). First the rifapentine model was developed. The fixed and random effects estimates of oral clearance (CL/F), volume of distribution (V/F), first-order absorption rate constant (ka), mean transit time (MTT), oral bioavailability (F) and number of hypothetical transit compartments (NN) were fixed and the 25-desacetyl rifapentine model was developed using all data assuming rifapentine was completely metabolized to 25-desacetyl rifapentine. Meal effects were investigated as categorical covariates and were found to be significant on the oral bioavailability.
Results: The pharmacokinetics of RFP were best described by a one-compartment model with first order absorption rate constant and time-varying clearance. 25-DRFP data were described by two-compartment model with time-varying clearance. 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.
Conclusions: As RFP has exposure-related activity, concomitant food should be considered when evaluating optimal RFP doses in RFP-based regimens, under the meal conditions that can feasibly be provided by tuberculosis control programs in high-burden countries.