Laboratory of Pharmacometrics, Center for Drug Clinical Research, Shanghai University of Chinese Medicine, Shanghai 201203, China.
Acta Pharmacol Sin. 2011 Jan;32(1):116-25. doi: 10.1038/aps.2010.169. Epub 2010 Dec 13.
To evaluate race differences in the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients using a population pharmacodynamic (PPD) model generated and validated using published clinical efficacy trials.
Published studies randomized trials with rosuvastatin treatment for at least 4 weeks in hypercholesterolemia patients were used for model building and validation. Population pharmacodynamic analyses were performed to describe the dose-response relationship with the mean values of LDL-C reduction (%) from dose-ranging trials using NONMEM software. Baseline LDL-C and race were analyzed as the potential covariates. Model robustness was evaluated using the bootstrap method and the data-splitting method, and Monte Carlo simulation was performed to assess the predictive performance of the PPD model with the mean effects from the one-dose trials.
Of the 36 eligible trials, 14 dose-ranging trials were used in model development and 22 one-dose trials were used for model prediction. The dose-response of rosuvastatin was successfully described by a simple E(max) model with a fixed E(0), which provided a common E(max) and an approximate twofold difference in ED(50) for Westerners and Asians. The PPD model was demonstrated to be stable and predictive.
The race differences in the pharmacodynamics of rosuvastatin are consistent with those observed in the pharmacokinetics of the drug, confirming that there is no significant difference in the exposure-response relationship for LDL-C reduction between Westerners and Asians. The study suggests that for a new compound with a mechanism of action similar to that of rosuvastatin, its efficacy in Western populations plus its pharmacokinetics in bridging studies in Asian populations may be used to support a registration of the new compound in Asian countries.
利用基于发表的临床疗效试验构建和验证的群体药代动力学（PPD）模型，评估西方和亚洲高胆固醇血症患者中瑞舒伐他汀药效学的种族差异。
使用发表的研究，即至少有 4 周瑞舒伐他汀治疗的高胆固醇血症患者的随机对照试验，用于模型构建和验证。使用 NONMEM 软件对来自剂量范围试验的 LDL-C 降低（%）的均值进行群体药效学分析，以描述剂量-反应关系。采用基线 LDL-C 和种族作为潜在协变量进行分析。采用自举法和数据分割法评估模型稳健性，并通过蒙特卡罗模拟评估来自单剂量试验的均值效应的 PPD 模型的预测性能。
在 36 项合格试验中，有 14 项剂量范围试验用于模型开发，有 22 项单剂量试验用于模型预测。瑞舒伐他汀的剂量-反应成功地通过具有固定 E(0)的简单 E(max)模型进行描述，该模型提供了一个共同的 E(max)和西方人和亚洲人之间 ED(50)的近似两倍差异。PPD 模型被证明是稳定和可预测的。
瑞舒伐他汀药效学的种族差异与药物药代动力学观察到的差异一致，证实了西方人和亚洲人在 LDL-C 降低的暴露-反应关系方面没有显著差异。该研究表明，对于一种作用机制与瑞舒伐他汀类似的新型化合物，可以使用其在西方人群中的疗效加上在亚洲人群中的桥接研究中的药代动力学来支持该新型化合物在亚洲国家的注册。
