Linezolid population pharmacokinetics in South African adults with drug-resistant tuberculosis.

Abstract

BACKGROUND Linezolid is widely used for drug-resistant tuberculosis (DR-TB) but has a narrow therapeutic index. To inform dose optimisation, we aimed to characterise the population pharmacokinetics of linezolid in South African participants with DR-TB and explore the effect of covariates, including HIV-co-infection, on drug exposure. METHODS Data were obtained from pharmacokinetic sub-studies in a randomised controlled trial and an observational cohort study, both of which enrolled adults with drug-resistant pulmonary tuberculosis. Participants underwent intensive and sparse plasma sampling. We analyzed linezolid concentration data using non-linear mixed-effects modelling and performed simulations to estimate attainment of putative efficacy and toxicity targets. RESULTS 124 participants provided 444 plasma samples; 116 were on the standard daily dose of 600 mg, while 19 had dose reduction to 300 mg due to adverse events. Sixty-one participants were female, 71 were HIV-positive, and median weight was 56 kg (IQR 50 - 63). In the final model, typical values for clearance and central volume were 3.57 L/h and 40.2 L, respectively. HIV co-infection had no significant effect on linezolid exposure. Simulations showed that 600 mg dosing achieved the efficacy target (f AUC0-24h/MIC > 119 at MIC level of 0.5 mg/L) with 96% probability but had 56% probability of exceeding safety target (trough24h > 2 mg/L). The 300 mg dose did not achieve adequate efficacy exposures. CONCLUSION Our model characterised population pharmacokinetics of linezolid in South African patients with DR-TB and supports the 600 mg daily dose with safety monitoring.