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Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China

Bedaquiline has been widely used as a part of combination dosage regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB) patients with limited options. Although the effectiveness and safety of bedaquiline have been demonstrated in clinical trials, limited studies have investigated th...

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Autores principales: Zou, Jin, Chen, Shuyan, Rao, Weiqiao, Fu, Liang, Zhang, Jiancong, Liao, Yunli, Zhang, Ying, Lv, Ning, Deng, Guofang, Yang, Shijin, Lin, Liang, Li, Lujin, Liu, Siqi, Qu, Jiuxin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578397/
https://www.ncbi.nlm.nih.gov/pubmed/36106884
http://dx.doi.org/10.1128/aac.00811-22
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author Zou, Jin
Chen, Shuyan
Rao, Weiqiao
Fu, Liang
Zhang, Jiancong
Liao, Yunli
Zhang, Ying
Lv, Ning
Deng, Guofang
Yang, Shijin
Lin, Liang
Li, Lujin
Liu, Siqi
Qu, Jiuxin
author_facet Zou, Jin
Chen, Shuyan
Rao, Weiqiao
Fu, Liang
Zhang, Jiancong
Liao, Yunli
Zhang, Ying
Lv, Ning
Deng, Guofang
Yang, Shijin
Lin, Liang
Li, Lujin
Liu, Siqi
Qu, Jiuxin
author_sort Zou, Jin
collection PubMed
description Bedaquiline has been widely used as a part of combination dosage regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB) patients with limited options. Although the effectiveness and safety of bedaquiline have been demonstrated in clinical trials, limited studies have investigated the significant pharmacokinetics and the impact of genotype on bedaquiline disposition. Here, we developed a population pharmacokinetic model of bedaquiline to describe the concentration-time data from Chinese adult patients diagnosed with MDR-TB. A total of 246 observations were collected from 99 subjects receiving the standard recommended dosage. Bedaquiline disposition was well described by a one-compartment model with first-order absorption. Covariate modeling identified that gamma-glutamyl transferase (GGT) and the single-nucleotide polymorphism (SNP) rs319952 in the AGBL4 gene were significantly associated with the apparent clearance of bedaquiline. The clearance (CL/F) was found to be 1.4 L/h lower for subjects with allele GG in SNP rs319952 than for subjects with alleles AG and AA and to decrease by 30% with a doubling in GGT. The model-based simulations were designed to assess the impact of GGT/SNP rs319952 on bedaquiline exposure and showed that patients with genotype GG in SNP rs319952 and GGT ranging from 10 to 50 U/L achieved the targeted maximum serum concentration at steady state (C(max,ss)). However, when GGT was increased to 100 U/L, C(max,ss) was 1.68-fold higher than the highest concentration pursued. The model developed provides the consideration of genetic polymorphism and hepatic function for bedaquiline dosage in MDR-TB adult patients.
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spelling pubmed-95783972022-10-19 Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China Zou, Jin Chen, Shuyan Rao, Weiqiao Fu, Liang Zhang, Jiancong Liao, Yunli Zhang, Ying Lv, Ning Deng, Guofang Yang, Shijin Lin, Liang Li, Lujin Liu, Siqi Qu, Jiuxin Antimicrob Agents Chemother Pharmacology Bedaquiline has been widely used as a part of combination dosage regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB) patients with limited options. Although the effectiveness and safety of bedaquiline have been demonstrated in clinical trials, limited studies have investigated the significant pharmacokinetics and the impact of genotype on bedaquiline disposition. Here, we developed a population pharmacokinetic model of bedaquiline to describe the concentration-time data from Chinese adult patients diagnosed with MDR-TB. A total of 246 observations were collected from 99 subjects receiving the standard recommended dosage. Bedaquiline disposition was well described by a one-compartment model with first-order absorption. Covariate modeling identified that gamma-glutamyl transferase (GGT) and the single-nucleotide polymorphism (SNP) rs319952 in the AGBL4 gene were significantly associated with the apparent clearance of bedaquiline. The clearance (CL/F) was found to be 1.4 L/h lower for subjects with allele GG in SNP rs319952 than for subjects with alleles AG and AA and to decrease by 30% with a doubling in GGT. The model-based simulations were designed to assess the impact of GGT/SNP rs319952 on bedaquiline exposure and showed that patients with genotype GG in SNP rs319952 and GGT ranging from 10 to 50 U/L achieved the targeted maximum serum concentration at steady state (C(max,ss)). However, when GGT was increased to 100 U/L, C(max,ss) was 1.68-fold higher than the highest concentration pursued. The model developed provides the consideration of genetic polymorphism and hepatic function for bedaquiline dosage in MDR-TB adult patients. American Society for Microbiology 2022-09-15 /pmc/articles/PMC9578397/ /pubmed/36106884 http://dx.doi.org/10.1128/aac.00811-22 Text en Copyright © 2022 Zou et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Pharmacology
Zou, Jin
Chen, Shuyan
Rao, Weiqiao
Fu, Liang
Zhang, Jiancong
Liao, Yunli
Zhang, Ying
Lv, Ning
Deng, Guofang
Yang, Shijin
Lin, Liang
Li, Lujin
Liu, Siqi
Qu, Jiuxin
Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China
title Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China
title_full Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China
title_fullStr Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China
title_full_unstemmed Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China
title_short Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China
title_sort population pharmacokinetic modeling of bedaquiline among multidrug-resistant pulmonary tuberculosis patients from china
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578397/
https://www.ncbi.nlm.nih.gov/pubmed/36106884
http://dx.doi.org/10.1128/aac.00811-22
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