Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients

Pretomanid is a nitroimidazole antibiotic in late-phase clinical testing as a component of several novel antituberculosis (anti-TB) regimens. A population pharmacokinetic model for pretomanid was constructed using a Bayesian analysis of data from two phase 2 studies, PA-824-CL-007 and PA-824-CL-010, conducted with adult (median age, 27 years) patients in Cape Town, South Africa, with newly diagnosed pulmonary TB. Combined, these studies included 63 males and 59 females administered once-daily oral pretomanid doses of 50, 100, 150, 200, 600, 1,000, or 1,200 mg for 14 days. The observed pretomanid plasma concentration-time profiles for all tested doses were described by a one-compartment model with first-order absorption and elimination and a sigmoidal bioavailability dependent on dose, time, and the pre-dose fed state. Allometric scaling with body weight (normalized to 70 kg) was used 0 for volume of distribution and clearance, with the scaling exponents equal to 1 and 3/4, respectively. The posterior population geometric means for the clearance and volume of distribution allometric constants were 4.8 +/- 0.2 liters/h and 130 +/- 5 liters, respectively, and the posterior population geometric mean for the half- maximum-effect dose for the reduction of bioavailability was 450 +/- 50 mg. Interin-dividual variability, described by the percent coefficient of variation, was 32% +/- 3% for clearance, 17% +/- 4% for the volume of distribution, and 74% +/- 9% for the half- maximum-effect dose. This model provides a dose-exposure relationship for preto- manid in adult TB patients with potential applications to dose selection in individuals and to further clinical testing of novel pretomanid-containing anti-TB regimens.