Effect of a High-Calorie,High-Fat Meal on the Bioavailability and Pharmacokinetics of PA-824 in Healthy Adult Subjects

PA-824 is a novel nitroimidazo-oxazine being developed as an antituberculosis agent. Two randomized studies evaluated the pharmacokinetics and safety of a single oral dose of PA-824 administered to healthy adult subjects 30 min after a high-calorie, high-fat meal (fed state) versus after a minimum 10-h fast (fasted state). A total of 48 subjects were dosed in the two studies in a randomized crossover design with PA-824 at dose levels of 50, 200, or 1,000 mg in the fed state or fasted state. After the administration of PA-824, the geometric mean ratios of C_max and AUC_0–∞ revealed an increase in exposure with the addition of a high-calorie, high-fat meal compared to the fasted state by 140 and 145% at 50 mg, 176 and 188% at 200 mg, and 450 and 473% at 50, 200, and 1,000 mg, respectively. The median T_max in the fed state was 4 h for the 50-mg dose and 5 h for the 200- and 1,000-mg doses. In the fasted state, the median T_max was 4 h for the 50- and 200-mg doses and 6.5 h for the 1,000-mg dose. All doses were well tolerated, and no serious adverse events occurred in either study. (This study has been registered at ClinicalTrials.gov under registration numbers {"type":"clinical-trial","attrs":{"text":"NCT01828827","term_id":"NCT01828827"}}NCT01828827 and {"type":"clinical-trial","attrs":{"text":"NCT01830439","term_id":"NCT01830439"}}NCT01830439.)