Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients [PublishAheadOfPrint]

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 newly diagnosed adult (median age 27 years) pulmonary TB patients in Cape Town, South Africa. Combined, these studies included 63 males and 59 females administered once daily oral pretomanid doses of 50, 100, 150, 200, 600, 1000, or 1200 mg for 14 days. The observed pretomanid 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 predose fed state. Allometric scaling with body weight (normalized to 70 kg) was used for volume of distribution and clearance, with scaling exponents of 1 and 3/4, respectively. The posterior population geometric means for clearance and volume of distribution allometric constants were 4.8±0.2 L/h and 130±5 L, respectively, and 450±50 mg for the half-maximum effect dose for reduction of bioavailability. Interindividual variability, described by percent coefficient of variation, was 32±3% for clearance, 17±4% for volume of distribution, and 74±9% for half-maximum effect dose. This model provides a dose-exposure relationship for pretomanid in adult TB patients, with potential applications to dose selection in individuals and to further clinical testing of novel pretomanid-containing anti-TB regimens.

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