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 AUC
0-24h
/MIC
> 119 at MIC level of 0.5 mg/L) with 96% probability but had 56% probability of exceeding safety target (
trough
24h
> 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.
Population Pharmacokinetics of Bedaquiline and Metabolite M2 in Patients With Drug‐Resistant Tuberculosis: The Effect of Time‐Varying Weight and Albumin
