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

Abstract

Objectives: The oxazolidinone linezolid is an effective component of drug-resistant TB treatment, but its use is limited by toxicity and the optimum dose 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 (fAUC0-24:MIC >119 mg/L/h) and safety (fCmin <1.38 mg/L). We extracted individual-level linezolid PK data from existing studies on TB patients and performed meta-analysis, producing summary estimates of fAUC0-24 and fCmin 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 300 mg q12h and 600 mg q12h, but only 20.7% missed the safety target at 300 mg q12h versus 98.5% at 600 mg q12h. Although suggesting 300 mg 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 300 mg q24h and by 44.6% and 27.5%, respectively, at 600 mg q24h. However, the confounding effect of between-study heterogeneity on target attainment for q24h regimens was considerable.

Conclusions: Linezolid dosing at 300 mg q12h may retain the efficacy of the 600 mg q12h licensed dosing with improved safety. Data to evaluate commonly used 300 mg q24h and 600 mg q24h doses are limited. Comprehensive, prospectively obtained PK/PD data for linezolid doses in drug-resistant TB treatment are required.

Figure 1.

PRISMA flowchart of included and excluded studies for the meta-analysis of existing linezolid PK data in TB therapy.

Figure 2.

Forest plot of included studies for meta-analysis of fAUC_0–24 at different doses of linezolid. Sampling timepoints in brackets were not assessed for all patients.

Figure 3.

Forest plot of included studies for meta-analysis of fC_min at different doses of linezolid. Sampling timepoints in brackets were not assessed for all patients.

Figure 4.

Probability density distributions of the attainment of linezolid fAUC_0–24:MIC >119 mg/L/h (vertical line) in a Monte Carlo simulation of 100 000 patients at different doses of linezolid, based on a published MIC distribution and summary AUC_0–24 from a meta-analysis of published data.

Figure 5.

Probability density distributions of the attainment of linezolid fAUC_0–24:MIC >119 mg/L/h (vertical line) in a Monte Carlo simulation of 100 000 patients at different doses of linezolid, based on a published MIC distribution and summary AUC_0–24 in a sensitivity analysis imputing individual studies at the 300 mg q24h and 600 mg q24h doses separately.