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

Zou, Jin1; Chen, Shuyan2,3; Rao, Weiqiao4; Fu, Liang5; Zhang, Jiancong1; Liao, Yunli4; Zhang, Ying1; Lv, Ning1; Deng, Guofang5; Yang, Shijin1; Lin, Liang4; Li, Lujin6; Liu, Siqi4; Qu, Jiuxin1

2022-09-01

10.1128/aac.00811-22

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY   Impact Factor & Quartile

0066-4804

1098-6596

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,C-ss). However, when GGT was increased to 100 U/L, C-max,C-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.

population pharmacokinetics bedaquiline multidrug-resistant tuberculosis GGT rs319952

SCI

English

First ; Corresponding

Guangdong Province Science and Technology Project (Tuberculosis)[2020B1111170014] ; Guangdong Basic and Applied Basic Research Foundation[2020A1515010586] ; Science and Technology Program of Shenzhen["JCYJ20190809144005609","JCYJ20210324131212034","JCYJ20180228162112889"] ; Third People's Hospital of Shenzhen["G2021014","G2021015"] ; Shenzhen Science and Technology Innovation Committee (SZSTI)[2021(287)] ; State Key Laboratory of Infectious Disease Prevention and Control[2019SKLID302]

Microbiology ; Pharmacology & Pharmacy

Microbiology ; Pharmacology & Pharmacy

WOS:000854064500001

AMER SOC MICROBIOLOGY

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Natl Clin Res Ctr Infect Dis, Dept Clin Lab, Shenzhen, Peoples R China
2.Univ Chinese Acad Sci, Coll Life Sci, Beijing, Peoples R China
3.Southern Univ Sci & Techno, Shenzhen Peoples Hosp 3, Natl Clin Res Ctr Infect Dis, Hosp 2, Shenzhen, Peoples R China
4.BGI Shenzhen, Shenzhen, Peoples R China
5.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Natl Clin Res Ctr Infect Dis, Div Pulm Dis Dept 2, Shenzhen, Peoples R China
6.Shanghai Univ Tradit Chinese Med, Ctr Drug Clin Res, Shanghai, Peoples R China

Zou, Jin,Chen, Shuyan,Rao, Weiqiao,et al. Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China[J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2022.

Zou, Jin.,Chen, Shuyan.,Rao, Weiqiao.,Fu, Liang.,Zhang, Jiancong.,...&Qu, Jiuxin.(2022).Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China.ANTIMICROBIAL AGENTS AND CHEMOTHERAPY.

Zou, Jin,et al."Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China".ANTIMICROBIAL AGENTS AND CHEMOTHERAPY (2022).