Modeling and Simulation of Pretomanid Pharmacodynamics in Pulmonary Tuberculosis Patients

Pretomanid (PA-824) is a nitroimidazole in clinical testing for the treatment of tuberculosis. A population pharmacodynamic model for pretomanid was developed using a Bayesian analysis of efficacy data from two early bactericidal activity (EBA) studies, PA-824-CL-007 and PA-824-CL-010, conducted in Cape Town, South Africa. The two studies included 122 adult male and female participants with newly diagnosed pulmonary tuberculosis who received once-daily oral pretomanid doses of either 50, 100, 150, 200, 600, 1,000, or 1,200 mg for 14 days. The structural model described capacity-limited growth and saturable drug-induced bacterial killing with separate rate equations for sputum solid culture CFU counts and liquid culture time to positivity (TTP) that were linked through a time constant. The posterior population geometric means and interindividual variability coefficients of variation were, respectively, 0.152 +/- 0.013 log(10) CFU/ml sputum/day and 54% +/- 6% for the maximum kill rate constant, 770 +/- 140 ng/ml and 48% +/- 17% for the pretomanid half-maximum effect plasma concentration, and 20.4 +/- 1.0 h and 20.8% +/- 0.1% for the time constant of proportionality between the CFU and TTP rate equations. Model simulations showed once-daily pretomanid at 100, 200, and 300 mg attained 58, 73, and 80%, respectively, of an expected maximum 14-day EBA of 0.136 log 10 CFU/ml sputum/day. These results establish a pretomanid exposure-efficacy relationship with dual outcomes for CFU counts and TTP and with potential applications to dose optimization of pretomanid-containing regimens.