Linezolid population pharmacokinetics in south african adults with drug-resistant tuberculosis

Mahmoud Tareq Abdelwahab, Sean Wasserman, James C.M. Brust, Keertan Dheda, Lubbe Wiesner, Neel R. Gandhi, Robin M. Warren, Frederick A. Sirgel, Graeme Meintjes, Gary Maartens, Paolo Denti

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Linezolid is widely used for drug-resistant tuberculosis (DR-TB) but has a narrow therapeutic index. To inform dose optimization, we aimed to characterize the population pharmacokinetics of linezolid in South African participants with DR-TB and explore the effect of covariates, including HIV coinfection, on drug exposure. Data were obtained from pharmacokinetic substudies in a randomized 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 nonlinear mixed-effects modeling and performed simulations to estimate attainment of putative efficacy and toxicity targets. A total of 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 their median weight was 56 kg (interquartile range [IQR], 50 to 63). In the final model, typical values for clearance and central volume were 3.57 liters/h and 40.2 liters, respectively. HIV coinfection had no significant effect on linezolid exposure. Simulations showed that 600-mg dosing achieved the efficacy target (area under the concentration-time curve for the free, unbound fraction of the drug [fAUC0 - 24h=minimal inhibitory concentration =MIC] . 119 at a MIC level of 0.5 mg/liter) with 96% probability but had 56% probability of exceeding safety target (trough24h . 2mg=literÞ. The 300-mg dose did not achieve adequate efficacy exposures. Our model characterized population pharmacokinetics of linezolid in South African patients with DR-TB and supports the 600-mg daily dose with safety monitoring.

Original languageEnglish (US)
Article numbere01381-21
JournalAntimicrobial agents and chemotherapy
Volume65
Issue number12
DOIs
StatePublished - Dec 2021

Keywords

  • Modeling and simulation
  • NONMEM
  • Optimized dosing regimen
  • PopPK/ PD
  • Population pharmacokinetics
  • Tuberculosis

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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