临床药代动力学中蓄积指数的计算方法及其评价

目的: 多次给药的蓄积一般由药动学的蓄积指数(Rac)来表达,但计算Rac有多种方法,本文对此进行分析和评价,以确定合理的方法。方法: 计算机模拟蒿乙醚真实实验的单、多次给药的血药浓度经时变化,分别采用AUC法、C_max法、C_trough法和模型法计算R_ac,采用Bootstrap抽样法评价各法的优缺点及适用条件。结果: AUC法和C_max法较C_trough法和模型法更为稳定,模型法计算值偏高。药效或毒性呈浓度依赖性者,宜用C_max法,而药效或毒性时间依赖性和体内药量依赖性时,宜用AUC法。结论: 药物蓄积与有效性和安全性均相关,R_ac计算方法需根据药物特性进行合理选择。

Evaluation and calculation of the accumulation index in clinical pharmacokinetics

AIM: To analyze and evaluate the accumulation index (R_ac) in clinical pharmacokinetics of multiple dosing administrations in order to obtain one reasonable method. METHODS: The plasma concentration-time data of arteether was simulated for 1000 subjects in multiple doses administration. The 20-40 subjects were sampled for 1000 time by the Boostrap method and values of R_ac were calculated by the AUC, C_max, C_trough and model. The values of R_ac were evaluated by their distributions. RESULTS: The AUC and C_max method were more stable than the C_trough and model method. If the efficacy or toxicity was related with the concentration, it was appropriate to use the C_max method, and if the efficacy or toxicity was related with the time, it was appropriate to use the AUC method. CONCLUSION: The drug accumulation is related with effectiveness and safety, and the reasonable choice of R_ac calculation method should be based on drug and data characteristics.