Correlations among the plasma concentrations of first-line anti-tuberculosis drugs and the physiological parameters influencing concentrations

Lin Cheng; Ming Luo; Yan Guo; Yunfan Fan; Pengsen Wang; Gang Zhou; Shiwei Qin; Bangbi Weng; Peibo Li; Zhirui Liu; Songtao Liu

doi:10.3389/fphar.2023.1248331

Correlations among the plasma concentrations of first-line anti-tuberculosis drugs and the physiological parameters influencing concentrations

Front Pharmacol. 2023 Oct 6:14:1248331. doi: 10.3389/fphar.2023.1248331. eCollection 2023.

Authors

Lin Cheng^#¹, Ming Luo^#², Yan Guo^#³, Yunfan Fan², Pengsen Wang², Gang Zhou², Shiwei Qin¹, Bangbi Weng¹, Peibo Li², Zhirui Liu¹, Songtao Liu²

Affiliations

¹ Department of Pharmacy, the First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing, China.
² Chongqing Public Health Medical Center, Southwest University Public Health Hospital, Chongqing, China.
³ Department of Infectious Diseases, the First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing, China.

^# Contributed equally.

Abstract

Background: The plasma concentrations of the four most commonly used first-line anti-tuberculosis (TB) drugs, isoniazid (INH), rifampicin (RMP), ethambutol (EMB), and pyrazinamide (PZA), are often not within the therapeutic range. Insufficient drug exposure could lead to drug resistance and treatment failure, while excessive drug levels may lead to adverse reactions. The purpose of this study was to identify the physiological parameters influencing anti-TB drug concentrations. Methods: A retrospective cohort study was conducted. The 2-h plasma concentrations of the four drugs were measured by using the high-performance liquid chromatography-tandem mass spectrometry method. Results: A total of 317 patients were included in the study. The proportions of patients with INH, RMP, EMB, and PZA concentrations within the therapeutic range were 24.3%, 31.5%, 27.8%, and 18.6%, respectively. There were positive associations between the concentrations of INH and PZA and RMP and EMB, but negative associations were observed between the concentrations of INH and RMP, INH and EMB, RMP and PZA, and EMB and PZA. In the multivariate analysis, the influencing factors of the INH concentration were the PZA concentration, total bile acid (TBA), serum potassium, dose, direct bilirubin, prealbumin (PA), and albumin; those of the RMP concentration were PZA and EMB concentrations, weight, α-l-fucosidase (AFU), drinking, and dose; those of the EMB concentration were the RMP and PZA concentrations, creatinine, TBA and indirect bilirubin; and those of the PZA concentration were INH, RMP and EMB concentrations, sex, weight, uric acid and drinking. Conclusion: The complex correlations between the concentrations of the four first-line anti-TB drugs lead to a major challenge in dose adjustment to maintain all drugs within the therapeutic window. Levels of TBA, PA, AFU, and serum potassium should also be considered when adjusting the dose of the four drugs.

Keywords: drug concentration; ethambutol; isoniazid; pyrazinamide; rifampicin; tuberculosis.

Grants and funding

This work was supported by the Fund for the Traditional Chinese Medical Research Project of Science and Health of Chongqing, China (2019ZY3483); the Medical Research Project of Science and Health of Chongqing, China (2023MSXM107); Science and Technology Project of Shapingba District, Chongqing, China (Jcd202213, Jcd202214); Chongqing Clinical Pharmacy Key Specialties Construction Project, China. Funding by Senior Medical Talents Program of Chongqing for Young and Middle-aged.