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, median AUC2 was 63,733 g{middle dot}h/L, and median trough concentration was 1,965 g/L. 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, supporting the regimens efficacy across the study population. We developed a pretomanid population PK model and facilitated exploring robust PK-PD targets for PTA that remain valuable to support dose optimisation. There is an urgent need for further research to identify the optimal clinically relevant PK-PD index for pretomanid, especially within the context of combination therapy.