Population pharmacokinetics and target attainment of pretomanid in rifampicin-resistant tuberculosis patients

Pretomanid is a key component of the bedaquiline, pretomanid, linezolid with or without moxifloxacin (BPaL/M) regimen recommended for treatment of rifampicin-resistant tuberculosis (RR-TB). To support dose optimization and efficacy interpretation, we developed a pretomanid population pharmacokinetic (PK) model and evaluated exposure and probability of target attainment (PTA). Ninety-four RR-TB patients received daily oral pretomanid at 200 mg, and plasma samples were collected at multiple time points. Pretomanid concentrations were quantified using high-performance liquid chromatography-tandem mass spectrometry and PK modeling was performed using nlmixr2 in R. A one-compartment model with first-order absorption and elimination, and fat free mass allometric scaling best described the data. Typical clearance was 3.10 L/h (32.9%CV), median AUC₀₋₂₄ was 64,000 (31,000– 140,000) ng·h/ml, and the median maximum inter-dose concentration (Cmax) was 3,000 (1,000– 6,000) ng/ml. Pretomanid MICs for Mycobacterium tuberculosis in the TB-PRACTECAL trial were consistently below the provisional critical concentration, with a median of 0.125 mg/L. PK-Pharmacodynamic (PD) simulations indicated that nearly all participants achieved drug exposures exceeding %fT > MIC target, consistent with the regimen’s clinical efficacy across the study population. However, the AUC/MIC target was not achieved. We developed a pretomanid population PK model and facilitated exploring robustness of PK-PD targets for PTA. Our study confirmed the clinical relevance of the time dependent index and target, but further investigation is needed to determine whether the 167 AUC/MIC target is valid in patients or using translational pre-clinical experiments, especially within the context of combination therapy. Trial registry: Clinical Trials.gov, TRN: NCT04081077, Registration date: 4 September 2019.