PMID- 34543098 OWN - NLM STAT- MEDLINE DCOM- 20211203 LR - 20230719 IS - 1098-6596 (Electronic) IS - 0066-4804 (Print) IS - 0066-4804 (Linking) VI - 65 IP - 12 DP - 2021 Nov 17 TI - Linezolid Population Pharmacokinetics in South African Adults with Drug-Resistant Tuberculosis. PG - e0138121 LID - 10.1128/AAC.01381-21 [doi] LID - e01381-21 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 [[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. FAU - Abdelwahab, Mahmoud Tareq AU - Abdelwahab MT AUID- ORCID: 0000-0002-2134-8749 AD - Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa. FAU - Wasserman, Sean AU - Wasserman S AUID- ORCID: 0000-0002-3508-6719 AD - Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa. AD - 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. AD - Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa. FAU - Brust, James C M AU - Brust JCM AD - Division of General Internal Medicine, Department of Medicine, Albert Einstein College of Medicine & Montefiore Medical Center, Bronx, New York, USA. FAU - Dheda, Keertan AU - Dheda K AUID- ORCID: 0000-0001-7709-5341 AD - Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and University of Cape Town Lung Institute, Cape Town, South Africa. AD - South African Medical Research Council Centre for the Study of Antimicrobial Resistance, University of Cape Towngrid.7836.a, Cape Town, South Africa. AD - Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom. FAU - Wiesner, Lubbe AU - Wiesner L AUID- ORCID: 0000-0002-9070-8699 AD - Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa. FAU - Gandhi, Neel R AU - Gandhi NR AD - Departments of Epidemiology and Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA. AD - Division of Infectious Diseases, Department of Medicine, Emory School of Medicine, Emory University, Atlanta, Georgia, USA. FAU - Warren, Robin M AU - Warren RM AD - 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. FAU - Sirgel, Frederick A AU - Sirgel FA AD - 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. FAU - Meintjes, Graeme AU - Meintjes G AD - 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. FAU - Maartens, Gary AU - Maartens G AUID- ORCID: 0000-0003-3080-6606 AD - Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa. AD - 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. FAU - Denti, Paolo AU - Denti P AUID- ORCID: 0000-0001-7494-079X AD - Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa. LA - eng GR - MR/S03563X/1/MRC_/Medical Research Council/United Kingdom GR - UM1 AI068634/AI/NIAID NIH HHS/United States GR - R01 AI145679/AI/NIAID NIH HHS/United States GR - UL1 TR001073/TR/NCATS NIH HHS/United States GR - WT_/Wellcome Trust/United Kingdom GR - K43 TW011421/TW/FIC NIH HHS/United States GR - 109056/WT_/Wellcome Trust/United Kingdom GR - K24 AI155045/AI/NIAID NIH HHS/United States GR - UM1 AI068636/AI/NIAID NIH HHS/United States GR - D43 TW010559/TW/FIC NIH HHS/United States GR - 098316/WT_/Wellcome Trust/United Kingdom GR - K24 AI114444/AI/NIAID NIH HHS/United States GR - R01 AI114304/AI/NIAID NIH HHS/United States GR - P30 AI124414/AI/NIAID NIH HHS/United States GR - UL1 TR002556/TR/NCATS NIH HHS/United States GR - UM1 AI106701/AI/NIAID NIH HHS/United States PT - Journal Article PT - Observational Study PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210920 PL - United States TA - Antimicrob Agents Chemother JT - Antimicrobial agents and chemotherapy JID - 0315061 RN - 0 (Antitubercular Agents) RN - ISQ9I6J12J (Linezolid) SB - IM MH - Adult MH - Antitubercular Agents/therapeutic use MH - Black People MH - Female MH - *HIV Infections/drug therapy MH - Humans MH - Linezolid MH - *Tuberculosis, Multidrug-Resistant/drug therapy PMC - PMC8597769 OTO - NOTNLM OT - NONMEM OT - modeling and simulation OT - optimized dosing regimen OT - popPK/PD OT - population pharmacokinetics OT - tuberculosis EDAT- 2021/09/21 06:00 MHDA- 2021/12/15 06:00 PMCR- 2021/11/17 CRDT- 2021/09/20 17:15 PHST- 2021/09/21 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/09/20 17:15 [entrez] PHST- 2021/11/17 00:00 [pmc-release] AID - 01381-21 [pii] AID - aac.01381-21 [pii] AID - 10.1128/AAC.01381-21 [doi] PST - ppublish SO - Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0138121. doi: 10.1128/AAC.01381-21. Epub 2021 Sep 20.