Linezolid pharmacokinetics in MDR-TB: A systematic review, meta-analysis and Monte Carlo simulation

Objectives: The oxazolidinone linezolid is an effective component of drug-resistant TB treatment, but its use is limited by toxicity and the optimumdose is uncertain. Current strategies are not informed by clinical pharmacokinetic (PK)/pharmacodynamic (PD) data;we aimed to address this gap. Methods: We defined linezolid PK/PD targets for efficacy (fAUC _0-24 :MIC > 119 mg/L/h) and safety (fC _min < 1.38mg/L). We extracted individual-level linezolid PK data from existing studies on TB patients and performed meta-analysis, producing summary estimates of fAUC _0-24 and fC _min for published doses. Combining these with a published MIC distribution, we performed Monte Carlo simulations of target attainment. Results: The efficacy target was attained in all simulated individuals at 300mg q12h and 600mg q12h, but only 20.7% missed the safety target at 300mg q12h versus 98.5% at 600mg q12h. Although suggesting 300mg q12h should be used preferentially, these data were reliant on a single centre. Efficacy and safety targets were missed by 41.0% and 24.2%, respectively, at 300mg q24h and by 44.6% and 27.5%, respectively, at 600mg q24h. However, the confounding effect of between-study heterogeneity on target attainment for q24h regimens was considerable. Conclusions: Linezolid dosing at 300mg q12h may retain the efficacy of the 600mg q12h licensed dosing with improved safety. Data to evaluate commonly used 300mg q24h and 600mg q24h doses are limited. Comprehensive, prospectively obtained PK/PD data for linezolid doses in drug-resistant TB treatment are required.