TY - JOUR
T1 - Linezolid population pharmacokinetics in south african adults with drug-resistant tuberculosis
AU - Abdelwahab, Mahmoud Tareq
AU - Wasserman, Sean
AU - Brust, James C.M.
AU - Dheda, Keertan
AU - Wiesner, Lubbe
AU - Gandhi, Neel R.
AU - Warren, Robin M.
AU - Sirgel, Frederick A.
AU - Meintjes, Graeme
AU - Maartens, Gary
AU - Denti, Paolo
N1 - Publisher Copyright:
Copyright © 2021 American Society for Microbiology. All Rights Reserved.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Modeling and simulation
KW - NONMEM
KW - Optimized dosing regimen
KW - PopPK/ PD
KW - Population pharmacokinetics
KW - Tuberculosis
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U2 - 10.1128/AAC.01381-21
DO - 10.1128/AAC.01381-21
M3 - Article
C2 - 34543098
AN - SCOPUS:85119327483
SN - 0066-4804
VL - 65
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 12
M1 - e01381-21
ER -