Tranchand B, Amsellem C, Chatelut E, Freyer G, Iliadis A, Ligneau B, Trillet-Lenoir V, Canal P, Lochon I, Ardiet C J
Laboratoire de Pharmacocinétique, Centre Léon Bérard, Lyon, France.
Cancer Chemother Pharmacol. 1999;43(4):316-22. doi: 10.1007/s002800050901.
Etoposide (VP16), a widely used anticancer drug, is a topoisomerase II inhibitor. A number of studies have highlighted a correlation between hematologic toxicity and pharmacokinetic or physiological parameters. Other studies have also suggested that the anti-tumor response could be related to the plasma etoposide concentration. Therefore, it would seem of interest to individualize VP16 dose regimens on the basis of pharmacokinetic parameters. The aim of this study was to develop and validate a limited-sampling strategy allowing VP16 pharmacokinetic evaluation with minimal disturbance to the patient. A total of 34 patients (54 kinetics) received VP16 at various dose regimens, with doses ranging between 30 and 200 mg and infusion times varying between 0.5 and 2 h. The statistical characteristics of the pharmacokinetic parameters were assessed from the first courses of treatment performed in 23/34 patients; then the following three-sample protocol was designed: the end of the infusion and 5 and 24 h after the start of the infusion. For validation of the model the main pharmacokinetic parameters (clearance, half-lives, volume of distribution) were estimated in the 11 remaining patients by maximum-likelihood estimation (ML) and by Bayesian estimation (BE) using the three sampling times designed. Statistical comparison showed a good concordance between ML and BE estimates (the bias for clearance was -1.72%). The limited-sampling strategy presented herein can thus be used for accurate estimation of VP16 pharmacokinetic parameters.
依托泊苷（VP16）是一种广泛使用的抗癌药物，是一种拓扑异构酶II抑制剂。许多研究强调了血液学毒性与药代动力学或生理参数之间的相关性。其他研究也表明，抗肿瘤反应可能与血浆依托泊苷浓度有关。因此，根据药代动力学参数个体化VP16给药方案似乎很有意义。本研究的目的是开发并验证一种有限采样策略，以在对患者干扰最小的情况下进行VP16药代动力学评估。共有34例患者（54次药代动力学研究）接受了不同剂量方案的VP16治疗，剂量范围为30至200mg，输注时间在0.5至2小时之间变化。从23/34例患者的首次治疗疗程中评估药代动力学参数的统计特征；然后设计了以下三点采样方案：输注结束时以及输注开始后5小时和24小时。为了验证模型，使用设计的三个采样时间，通过最大似然估计（ML）和贝叶斯估计（BE）对其余11例患者的主要药代动力学参数（清除率、半衰期、分布容积）进行了估计。统计比较显示ML和BE估计之间具有良好的一致性（清除率的偏差为-1.72%）。因此，本文提出的有限采样策略可用于准确估计VP16药代动力学参数。
