Linezolid Population Pharmacokinetics in South African Adults with Drug-Resistant Tuberculosis.

Autor: Abdelwahab MT; Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa., Wasserman S; Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa.; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa.; Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa., Brust JCM; Division of General Internal Medicine, Department of Medicine, Albert Einstein College of Medicine & Montefiore Medical Center, Bronx, New York, USA., Dheda K; Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and University of Cape Town Lung Institute, Cape Town, South Africa.; South African Medical Research Council Centre for the Study of Antimicrobial Resistance, University of Cape Towngrid.7836.a, Cape Town, South Africa.; Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom., Wiesner L; Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa., Gandhi NR; Departments of Epidemiology and Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.; Division of Infectious Diseases, Department of Medicine, Emory School of Medicine, Emory University, Atlanta, Georgia, USA., Warren RM; DST-NRF Centre of Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch Universitygrid.11956.3a, Stellenbosch, South Africa., Sirgel FA; DST-NRF Centre of Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch Universitygrid.11956.3a, Stellenbosch, South Africa., Meintjes G; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa., Maartens G; Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa.; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa., Denti P; Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2021 Nov 17; Vol. 65 (12), pp. e0138121. Date of Electronic Publication: 2021 Sep 20.
DOI: 10.1128/AAC.01381-21
Abstrakt: 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 [[Formula: see text] at a MIC level of 0.5 mg/liter) with 96% probability but had 56% probability of exceeding safety target ([Formula: see text]. 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.
Databáze: MEDLINE