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Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis

Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment...

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Autores principales: Wu, Junzhen, Yang, Xinyi, Wu, Jufang, Wang, Jingjing, Wu, Hailan, Wang, Yu, Yuan, Hong, Yang, Huahui, Wang, Hailin, Zhang, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10040594/
https://www.ncbi.nlm.nih.gov/pubmed/36992830
http://dx.doi.org/10.3389/fphar.2023.1135007
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author Wu, Junzhen
Yang, Xinyi
Wu, Jufang
Wang, Jingjing
Wu, Hailan
Wang, Yu
Yuan, Hong
Yang, Huahui
Wang, Hailin
Zhang, Jing
author_facet Wu, Junzhen
Yang, Xinyi
Wu, Jufang
Wang, Jingjing
Wu, Hailan
Wang, Yu
Yuan, Hong
Yang, Huahui
Wang, Hailin
Zhang, Jing
author_sort Wu, Junzhen
collection PubMed
description Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally. Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data. Results: Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC(0–24h), 106.79 vs. 97.07 h μg/mL) of contezolid even though lower maximum concentration (C(max), 19.03 vs. 34.49 μg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae(0–48h)) and renal clearance (CL(R)) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower C(max), slightly lower AUC and Ae(0–48h) of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4 mg/L) in patients with moderate hepatic impairment. Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment. Clinical Trial Registration: https://chinadrugtrials.org.cn, identifier: CTR20171377.
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spelling pubmed-100405942023-03-28 Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis Wu, Junzhen Yang, Xinyi Wu, Jufang Wang, Jingjing Wu, Hailan Wang, Yu Yuan, Hong Yang, Huahui Wang, Hailin Zhang, Jing Front Pharmacol Pharmacology Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally. Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data. Results: Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC(0–24h), 106.79 vs. 97.07 h μg/mL) of contezolid even though lower maximum concentration (C(max), 19.03 vs. 34.49 μg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae(0–48h)) and renal clearance (CL(R)) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower C(max), slightly lower AUC and Ae(0–48h) of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4 mg/L) in patients with moderate hepatic impairment. Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment. Clinical Trial Registration: https://chinadrugtrials.org.cn, identifier: CTR20171377. Frontiers Media S.A. 2023-03-13 /pmc/articles/PMC10040594/ /pubmed/36992830 http://dx.doi.org/10.3389/fphar.2023.1135007 Text en Copyright © 2023 Wu, Yang, Wu, Wang, Wu, Wang, Yuan, Yang, Wang and Zhang. 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
Wu, Junzhen
Yang, Xinyi
Wu, Jufang
Wang, Jingjing
Wu, Hailan
Wang, Yu
Yuan, Hong
Yang, Huahui
Wang, Hailin
Zhang, Jing
Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis
title Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis
title_full Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis
title_fullStr Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis
title_full_unstemmed Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis
title_short Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis
title_sort dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10040594/
https://www.ncbi.nlm.nih.gov/pubmed/36992830
http://dx.doi.org/10.3389/fphar.2023.1135007
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