Van Kesteren Ch, Mathôt R A A, Raymond E, Armand J P, Dittrich Ch, Dumez H, Roché H, Droz J P, Punt C, Ravic M, Wanders J, Beijnen J H, Fumoleau P, Schellens J H M
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam.
J Clin Oncol. 2002 Oct 1;20(19):4065-73. doi: 10.1200/JCO.2002.01.005.
N-(3-Chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) is a novel sulfonamide anticancer agent currently in phase II clinical development for the treatment of solid tumors. Four phase I studies have been finalized, with E7070 administered at four different treatment schedules to identify the maximum-tolerated dose and the dose-limiting toxicities. Pharmacokinetic analyses of all studies revealed E7070 to have nonlinear pharmacokinetics. A population pharmacokinetic model was designed and validated to describe the pharmacokinetics of E7070 at all four treatment schedules and to identify the possible influences of patient characteristics on the pharmacokinetic parameters.
Plasma concentration-time data of all patients (n = 143) were fitted to several pharmacokinetic models using NONMEM. Seventeen covariables were investigated for their relation with individual pharmacokinetic parameters. A bootstrap procedure was performed to check the validity of the model.
The data were best described using a three-compartment model with nonlinear distribution to a peripheral compartment and two parallel pathways of elimination from the central compartment: a linear and a saturable pathway. Body-surface area (BSA) was significantly correlated to both the volume of distribution of the central compartment and to the maximal elimination capacity. The fits of 500 bootstrap replicates of the data set demonstrated the robustness of the developed population pharmacokinetic model.
A population pharmacokinetic model has been designed and validated that accurately describes the data of four phase I studies with E7070. Furthermore, it has been demonstrated that BSA-guided dosing for E7070 is important.
N-(3-氯-7-吲哚基)-1,4-苯二磺酰胺(E7070)是一种新型磺酰胺类抗癌药物,目前正处于治疗实体瘤的II期临床开发阶段。四项I期研究已经完成,E7070按照四种不同的治疗方案给药,以确定最大耐受剂量和剂量限制性毒性。所有研究的药代动力学分析表明E7070具有非线性药代动力学特征。设计并验证了一个群体药代动力学模型,以描述E7070在所有四种治疗方案下的药代动力学,并确定患者特征对药代动力学参数的可能影响。
使用NONMEM将所有患者(n = 143)的血浆浓度-时间数据拟合到几个药代动力学模型中。研究了17个协变量与个体药代动力学参数的关系。进行了自举程序以检查模型的有效性。
使用三室模型能最好地描述数据,该模型具有向外周室的非线性分布以及从中央室消除的两条平行途径:一条线性途径和一条饱和途径。体表面积(BSA)与中央室的分布容积和最大消除能力均显著相关。数据集的500次自举重复拟合证明了所开发的群体药代动力学模型的稳健性。
已经设计并验证了一个群体药代动力学模型,该模型准确描述了四项E7070的I期研究数据。此外,已经证明E7070的BSA指导给药很重要。