Pretomanid levels meet targets in rifampicin-resistant TB patients

Rifampicin-resistant tuberculosis (RR-TB) is a serious form of TB that needs effective combination treatment. The bedaquiline, pretomanid, linezolid with or without moxifloxacin (BPaL/M) regimen is recommended for RR-TB, and understanding how pretomanid behaves in the body helps doctors choose the best dose and interpret how well the drug will work. To support dose optimisation and efficacy interpretation, Bern-Thomas Nyang’wa and colleagues developed a population pharmacokinetic (PK) model for pretomanid and evaluated exposure and the probability of target attainment (PTA). The study enrolled 94 RR-TB patients who each received daily oral pretomanid at 200 mg. Blood samples were taken at multiple times to measure drug levels and build a model that describes how pretomanid is absorbed, distributed and eliminated. The work aimed to show whether the drug reaches concentrations likely to kill Mycobacterium tuberculosis in patients treated with the BPaL/M regimen, and to provide a tool researchers and clinicians can use to explore dosing questions and support decisions about pretomanid use in combination therapy.

The research team quantified pretomanid in plasma using high-performance liquid chromatography-tandem mass spectrometry and performed PK modeling using nlmixr2 in R. The data from the 94 patients were best described by a one-compartment model with first-order absorption and elimination, and fat free mass allometric scaling. From the model, typical clearance was 3.10 L/h. Measured exposure values included a median AUC₀₋₂₄ of 63,733 μg·h/L and a median trough concentration of 1,965 μg/L. The investigators compared these exposures to drug susceptibility results: pretomanid MICs for Mycobacterium tuberculosis in the TB-PRACTECAL trial were consistently below the provisional critical concentration, with a median MIC of 0.125 mg/L. PK-PD simulations using the model indicated that nearly all participants achieved drug exposures exceeding %fT>MIC, supporting that the dosing produced exposures likely to be effective. The model therefore enabled exploration of PTA and robust PK-PD targets to support dose optimisation.

These findings are important because they provide evidence that the standard 200 mg daily pretomanid dose produces drug levels that, in simulations, exceed key pharmacodynamic targets for nearly all patients in this study. By building a population PK model, the researchers created a practical tool to evaluate how patient factors like body composition could affect pretomanid exposure and the probability of reaching targets in the context of the BPaL/M regimen. That said, the authors stress an urgent need for further research to identify the optimal clinically relevant PK-PD index for pretomanid, especially when it is used in combination with other drugs. In other words, while the present work supports current dosing and offers a way to study dose-response relationships, additional studies are required to confirm which PK-PD measures best predict treatment success and to refine dosing recommendations within combination therapy settings.