Slotervaart Hospital, Department of Pharmacy and Pharmacology, Louwesweg 6, 1066 EC Amsterdam, The Netherlands.
J Clin Pharmacol. 2012 Mar;52(3):370-80. doi: 10.1177/0091270010397051. Epub 2011 Apr 19.
Intravenously administered docetaxel is approved for the treatment of various types of cancer. An oral regimen, in combination with ritonavir, is being evaluated in clinical trials. The pharmacokinetics of docetaxel are determined by the activity of the metabolizing enzyme cytochrome P450 3A (CYP3A) and the drug efflux transporter P-glycoprotein (P-gp). The effects of these proteins on the pharmacokinetics of docetaxel were investigated in different mouse models that lack 1 or both detoxifying systems. Docetaxel was given to these mice orally or intravenously with or without a strong CYP3A inhibitor, ritonavir. The data of these 2 preclinical studies were pooled and analyzed using nonlinear mixed-effects modeling. The results of the preclinical studies could be integrated successfully, with only a small difference in residual error (33% and 26%, respectively). Subsequently, the model was used to predict human exposure using allometric scaling and this was compared with clinical trial data. This model led to adequate predictions of docetaxel exposure in humans.
多西他赛经静脉给药获批用于多种类型的癌症治疗。一种口服制剂，与利托那韦联合使用，正在临床试验中进行评估。多西他赛的药代动力学由代谢酶细胞色素 P450 3A（CYP3A）和药物外排转运蛋白 P-糖蛋白（P-gp）的活性决定。在缺乏 1 种或 2 种解毒系统的不同小鼠模型中研究了这些蛋白对多西他赛药代动力学的影响。给这些小鼠口服或静脉注射多西他赛，同时或不使用强 CYP3A 抑制剂利托那韦。使用非线性混合效应模型对这 2 项临床前研究的数据进行了汇总和分析。这些临床前研究的结果可以成功整合，残差差异很小（分别为 33%和 26%）。随后，使用体表面积法对该模型进行了预测，并用临床研究数据进行了比较。该模型能够对人体多西他赛暴露情况进行充分预测。
