Effects of four different meal types on the population pharmacokinetics of single-dose rifapentine in healthy male volunteers

Abstract

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.

FIG. 1.

Illustration of the parent metabolite model. All rifapentine (RFP) is assumed to be converted to the major metabolite (25-DRFP). N₁ represents the first hypothetical transit compartment up to N_n compartment. k_tr is the transit rate constant. k_a is the absorption rate constant from the hypothetical drug depot compartment to plasma. k (calculated as CL/V) is the elimination rate constant of rifapentine. CL_m is the time-varying metabolite clearance. V_m represents volume of distribution of the metabolite. k34 is the first-order rate constant of the metabolite from plasma to the peripheral compartment, and k43 is the first-order rate constant of the metabolite from the peripheral compartment back to plasma.

FIG. 2.

Visual predictive check for the final (left) and metabolite (right) models. The lower, middle, and upper solid lines are the 5th, 50th, and 95th percentiles of the observed data, respectively. The dotted and dashed-dotted (50th percentile) lines around each percentile show the 95% confidence interval from the model prediction. The circles are the observed concentration-time data points.