Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Department of Pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands.
Clin Pharmacol Ther. 2018 Apr;103(4):674-683. doi: 10.1002/cpt.778. Epub 2017 Aug 7.
Accumulating evidence suggests that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics, and antimycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty-three pulmonary tuberculosis patients received 10, 20, 25, 30, 35, or 40 mg/kg rifampicin daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol in the second week. This study aimed at characterizing rifampicin pharmacokinetics observed in HIGHRIF1 using nonlinear mixed effects modeling. The final population pharmacokinetic model included an enzyme turnover model accounting for time-dependent elimination due to autoinduction, concentration-dependent clearance, and dose-dependent bioavailability. The relationship between clearance and concentration was characterized by a Michaelis-Menten relationship. The relationship between bioavailability and dose was described using an E relationship. The model will be key in determining exposure-response relationships for rifampicin and should be considered when designing future trials and when treating future patients with high-dose rifampicin.
越来越多的证据表明，增加利福平剂量可能会缩短结核病的治疗时间。PanACEA HIGHRIF1 试验评估了高达 40mg/kg 剂量的利福平的安全性、药代动力学和抗分枝杆菌活性。83 例肺结核患者接受了 10、20、25、30、35 或 40mg/kg 的利福平，每天一次，持续 2 周，第二周补充标准剂量的异烟肼、吡嗪酰胺和乙胺丁醇。本研究旨在使用非线性混合效应模型对 HIGHRIF1 中观察到的利福平药代动力学进行特征描述。最终的群体药代动力学模型包括一个酶周转模型，该模型考虑了由于自动诱导导致的时间依赖性消除、浓度依赖性清除和剂量依赖性生物利用度。清除率与浓度之间的关系通过米氏方程来描述。生物利用度与剂量之间的关系用 E 关系来描述。该模型将是确定利福平暴露-反应关系的关键，在设计未来的试验和治疗未来的高剂量利福平患者时应加以考虑。
