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Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India

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,...

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Autores principales: Resendiz-Galvan, Juan Eduardo, Arora, Prerna R., Abdelwahab, Mahmoud Tareq, Udwadia, Zarir F., Rodrigues, Camilla, Gupta, Amita, Denti, Paolo, Ashavaid, Tester F., Tornheim, Jeffrey A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9846493/
https://www.ncbi.nlm.nih.gov/pubmed/36686664
http://dx.doi.org/10.3389/fphar.2022.1081123
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author Resendiz-Galvan, Juan Eduardo
Arora, Prerna R.
Abdelwahab, Mahmoud Tareq
Udwadia, Zarir F.
Rodrigues, Camilla
Gupta, Amita
Denti, Paolo
Ashavaid, Tester F.
Tornheim, Jeffrey A.
author_facet Resendiz-Galvan, Juan Eduardo
Arora, Prerna R.
Abdelwahab, Mahmoud Tareq
Udwadia, Zarir F.
Rodrigues, Camilla
Gupta, Amita
Denti, Paolo
Ashavaid, Tester F.
Tornheim, Jeffrey A.
author_sort Resendiz-Galvan, Juan Eduardo
collection PubMed
description 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 ≤0.25 mg/L (61.5% of participant samples tested), while 600 mg daily would be required if MIC were 0.5 mg/L (29% of samples). While linezolid 300 mg daily is predicted to achieve effective targets for the majority of adults with MDR-TB, it failed to achieve the therapeutic target for 21% participants. A dose of 600 mg had a PTA >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.
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spelling pubmed-98464932023-01-19 Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India Resendiz-Galvan, Juan Eduardo Arora, Prerna R. Abdelwahab, Mahmoud Tareq Udwadia, Zarir F. Rodrigues, Camilla Gupta, Amita Denti, Paolo Ashavaid, Tester F. Tornheim, Jeffrey A. Front Pharmacol Pharmacology 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 ≤0.25 mg/L (61.5% of participant samples tested), while 600 mg daily would be required if MIC were 0.5 mg/L (29% of samples). While linezolid 300 mg daily is predicted to achieve effective targets for the majority of adults with MDR-TB, it failed to achieve the therapeutic target for 21% participants. A dose of 600 mg had a PTA >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. Frontiers Media S.A. 2023-01-04 /pmc/articles/PMC9846493/ /pubmed/36686664 http://dx.doi.org/10.3389/fphar.2022.1081123 Text en Copyright © 2023 Resendiz-Galvan, Arora, Abdelwahab, Udwadia, Rodrigues, Gupta, Denti, Ashavaid and Tornheim. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Resendiz-Galvan, Juan Eduardo
Arora, Prerna R.
Abdelwahab, Mahmoud Tareq
Udwadia, Zarir F.
Rodrigues, Camilla
Gupta, Amita
Denti, Paolo
Ashavaid, Tester F.
Tornheim, Jeffrey A.
Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India
title Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India
title_full Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India
title_fullStr Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India
title_full_unstemmed Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India
title_short Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India
title_sort pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in mumbai, india
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9846493/
https://www.ncbi.nlm.nih.gov/pubmed/36686664
http://dx.doi.org/10.3389/fphar.2022.1081123
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