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 colony forming unit (CFU) counts and liquid culture time to positivity (TTP) that were linked through a time constant. The posterior population geometric means and interindividual variability percent coefficients of variation were, respectively; 0.152±0.013 log₁₀ CFU/mL sputum/day and 54%±6% for the maximum kill rate constant, 20.4±1.0 h and 20.8%±0.1% for the time constant of proportionality between the CFU and TTP rate equations, and 770±140 ng/mL and 48%±17% for the pretomanid half-maximum effect plasma concentration. Model simulations showed once daily pretomanid at 100 mg, 200 mg, and 300 mg, attained 58%, 73%, and 80%, respectively, of an expected maximum 14-day EBA of 0.136 log₁₀CFU/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.