Linezolid population pharmacokinetics in rifampicin-resistant tuberculosis patients and interpretation challenges of the probability of target attainment
Abstract
Linezolid is a key component of the BPaLM regimen (bedaquiline, pretomanid, linezolid, and moxifloxacin), the recommended treatment for rifampicin-resistant tuberculosis (RR-TB). However, its optimal dosing and duration remain uncertain. To support dose optimization and efficacy interpretation, we developed a population pharmacokinetic (PK) model of linezolid and evaluated exposure and probability of target attainment (PTA). Ninety-four RR-TB patients received linezolid 600 mg daily for 16 weeks, followed by 300 mg daily for 8 weeks. Plasma samples were collected at multiple time points across 24 weeks and analyzed using high-performance liquid chromatography-tandem mass spectrometry. PK modeling was performed using nlmixr2 in R. A one-compartment model with first-order absorption and elimination, fat-free mass allometric scaling best described the data. Typical clearance and volume were 6.66 L/h and 58.8 L, respectively. Median AUC0-24 was 84.34 mg{middle dot}h/L at 600 mg and 46.36 mg{middle dot}h/L at 300 mg. Median trough concentrations were 0.71 mg/L and 0.39 mg/L, respectively. The PTA analysis showed that the 600 mg dose achieved the fAUC0-24/MIC target of 119 only for isolates with MICs [≤]0.25 mg/L, however our randomized controlled trial findings suggest that a step-down strategy from 600 mg to 300 mg daily maintains efficacy in RR-TB treatment despite the lower linezolid exposure. This highlights the need to revise current pharmacokinetic-pharmacodynamic (PK-PD)…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
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