PMID- 36686664 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230719 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 13 DP - 2022 TI - Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India. PG - 1081123 LID - 10.3389/fphar.2022.1081123 [doi] LID - 1081123 AB - Linezolid is an oxazolidinone used to treat multidrug-resistant tuberculosis (MDR-TB), including in the recently-endorsed shorter 6-month treatment regimens. Due to its narrow therapeutic index, linezolid is often either dose-adjusted or discontinued due to intolerance or toxicity during treatment, and the optimal balance between linezolid efficacy and toxicity remains unclear. India carries a significant burden of MDR-TB cases in the world, but limited information on the pharmacokinetics of linezolid and minimum inhibitory concentration (MIC) distribution is available from Indian MDR-TB patients. We enrolled participants from a tertiary care centre in Mumbai, India, treated for MDR-TB and receiving linezolid daily doses of 600 or 300 mg. Pharmacokinetic visits were scheduled between 1 and 15 months after treatment initiation to undergo intensive or sparse blood sampling. Linezolid concentration versus time data were analysed using non-linear mixed-effects modelling, with simulations to evaluate doses for different scenarios. We enrolled 183 participants (121 females), with a median age of 26 years (interquartile range [IQR] 21-35), weight 55.0 kg (IQR 45.6-65.8), and fat-free mass 38.7 kg (IQR 32.7-46.0). Linezolid pharmacokinetics was best described by a one-compartment model with first-order elimination allometrically scaled by fat-free mass and transit compartment absorption. The typical clearance value was 3.81 L/h. Simulations predicted that treatment with 300 mg daily achieves a high probability of target attainment (PTA) when linezolid MIC was 90% for all susceptible samples, but with a higher likelihood of exceeding toxicity thresholds (31% vs 9.6%). These data suggest potential benefit to individualized dosing taking host and microbial characteristics into account to improve the likelihood of treatment efficacy while minimizing risk of toxicity from linezolid for the treatment of MDR-TB. Further prospective evaluation in different clinical settings is urgently needed to inform safety and efficacy of these lower doses. CI - Copyright (c) 2023 Resendiz-Galvan, Arora, Abdelwahab, Udwadia, Rodrigues, Gupta, Denti, Ashavaid and Tornheim. FAU - Resendiz-Galvan, Juan Eduardo AU - Resendiz-Galvan JE AD - Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. FAU - Arora, Prerna R AU - Arora PR AD - Research Laboratories, P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India. FAU - Abdelwahab, Mahmoud Tareq AU - Abdelwahab MT AD - Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. FAU - Udwadia, Zarir F AU - Udwadia ZF AD - Division of Respiratory Medicine, P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India. FAU - Rodrigues, Camilla AU - Rodrigues C AD - Research Laboratories, P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India. FAU - Gupta, Amita AU - Gupta A AD - Center for Infectious Diseases in India, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, United States. AD - Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, United States. AD - Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States. FAU - Denti, Paolo AU - Denti P AD - Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. FAU - Ashavaid, Tester F AU - Ashavaid TF AD - Research Laboratories, P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India. FAU - Tornheim, Jeffrey A AU - Tornheim JA AD - Center for Infectious Diseases in India, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, United States. AD - Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, United States. AD - Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States. LA - eng GR - K23 AI135102/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20230104 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC9846493 OTO - NOTNLM OT - MDR-TB (multidrug resistant-TB) OT - NONMEM modelling OT - linezolid (LZD) OT - pharmacokinetics OT - pharmacometrics COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/01/24 06:00 MHDA- 2023/01/24 06:01 PMCR- 2023/01/04 CRDT- 2023/01/23 04:54 PHST- 2022/10/26 00:00 [received] PHST- 2022/12/12 00:00 [accepted] PHST- 2023/01/23 04:54 [entrez] PHST- 2023/01/24 06:00 [pubmed] PHST- 2023/01/24 06:01 [medline] PHST- 2023/01/04 00:00 [pmc-release] AID - 1081123 [pii] AID - 10.3389/fphar.2022.1081123 [doi] PST - epublish SO - Front Pharmacol. 2023 Jan 4;13:1081123. doi: 10.3389/fphar.2022.1081123. eCollection 2022.