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<p>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&#xa0;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&#xa0;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 <i>Mycobacterium tuberculosis</i> in the TB-PRACTECAL trial were consistently below the provisional critical concentration, with a median of 0.125&#xa0;mg/L. PK-Pharmacodynamic (PD) simulations indicated that nearly all participants achieved drug exposures exceeding %fT &gt; 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.</p><p><b>Trial registry</b>: Clinical Trials.gov, TRN: NCT04081077, Registration date: 4 September 2019.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月31日

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  • Bern-Thomas Nyang’wa,
  • Ilaria Motta,
  • Ronelle Moodliar,
  • Varvara Solodovnikova,
  • Shakira Rajaram,
  • Mohammed Rasool,
  • Catherine Berry,
  • Zhonghui Huang,
  • Geraint Davies,
  • David A.J. Moore,
  • Frank Kloprogge

摘要

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.