Cheng Lin, Luo Ming, Guo Yan, Fan Yunfan, Wang Pengsen, Zhou Gang, Qin Shiwei, Weng Bangbi, Li Peibo, Liu Zhirui, Liu Songtao
Department of Pharmacy, the First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing, China.
Chongqing Public Health Medical Center, Southwest University Public Health Hospital, Chongqing, China.
Front Pharmacol. 2023 Oct 6;14:1248331. doi: 10.3389/fphar.2023.1248331. eCollection 2023.
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. 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. 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. 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.
四种最常用的一线抗结核药物，即异烟肼（INH）、利福平（RMP）、乙胺丁醇（EMB）和吡嗪酰胺（PZA）的血浆浓度常常不在治疗范围内。药物暴露不足可能导致耐药性和治疗失败，而药物水平过高可能导致不良反应。本研究的目的是确定影响抗结核药物浓度的生理参数。进行了一项回顾性队列研究。采用高效液相色谱-串联质谱法测量四种药物的2小时血浆浓度。共有317名患者纳入研究。INH、RMP、EMB和PZA浓度在治疗范围内的患者比例分别为24.3%、31.5%、27.8%和18.6%。INH与PZA的浓度之间以及RMP与EMB的浓度之间存在正相关，但在INH与RMP、INH与EMB、RMP与PZA以及EMB与PZA的浓度之间观察到负相关。在多变量分析中，INH浓度的影响因素为PZA浓度、总胆汁酸（TBA）、血清钾、剂量、直接胆红素、前白蛋白（PA）和白蛋白；RMP浓度的影响因素为PZA和EMB浓度、体重、α-L-岩藻糖苷酶（AFU）、饮酒情况和剂量；EMB浓度的影响因素为RMP和PZA浓度、肌酐、TBA和间接胆红素；PZA浓度的影响因素为INH、RMP和EMB浓度、性别、体重、尿酸和饮酒情况。四种一线抗结核药物浓度之间的复杂相关性给剂量调整带来了重大挑战，以确保所有药物都维持在治疗窗内。在调整这四种药物的剂量时，还应考虑TBA、PA、AFU和血清钾的水平。
