Department of Digestive Surgery, Centre Hospitalo-Universitaire Lyon Sud, Pierre Bénite cedex, France.
J Clin Pharmacol. 2011 Jan;51(1):9-18. doi: 10.1177/0091270009360980. Epub 2010 Feb 19.
The aim of this work was to study the pharmacokinetics of cisplatinum during closed abdominal hyperthermic intraperitoneal chemotherapy (HIPEC) using a population pharmacokinetics approach. Forty patients were treated between January 2003 and December 2004. Peritoneal and blood concentrations of cisplatinum were used to develop a pharmacokinetic model of the peritoneal and plasma compartments using NONMEM software. Different covariables were analyzed to identify those that explain part of the interindividual variability of the pharmacokinetic parameters. Relationships between the area under the concentration-time curve (AUC) and hematological and renal toxicity and efficiency were explored. The pharmacokinetics of cisplatinum were modeled with a 3-compartment model. Estimations of the plasma and peritoneal pharmacokinetic parameters were obtained. No clinical or biological covariates correlated with these parameters. No direct relationship between the AUC of the peritoneal or plasma and toxicity or efficiency was demonstrated. The pharmacokinetics during HIPEC could be modeled with a 3-compartment model using a population pharmacokinetics approach. This work is the basis of further studies. Notably, studies including new patients will analyze the impact of abdominal cavity volume and the variation of the abdominal pressure during HIPEC on the pharmacokinetics of cisplatinum.
本研究旨在采用群体药代动力学方法研究顺铂在闭腹腹腔内热灌注化疗（HIPEC）中的药代动力学。2003 年 1 月至 2004 年 12 月期间，40 名患者接受了治疗。使用 NONMEM 软件，通过对顺铂的腹膜和血液浓度进行分析，建立了腹膜和血浆腔室的药代动力学模型。分析了不同的协变量，以确定那些能部分解释药代动力学参数个体间变异性的协变量。探讨了 AUC 与血液学和肾毒性及疗效之间的关系。采用三室模型对顺铂的药代动力学进行建模。获得了血浆和腹膜药代动力学参数的估算值。没有临床或生物学协变量与这些参数相关。腹膜或血浆 AUC 与毒性或疗效之间没有直接关系。采用群体药代动力学方法可以用三室模型对 HIPEC 期间的药代动力学进行建模。这项工作是进一步研究的基础。值得注意的是，包括新患者的研究将分析腹腔容量和 HIPEC 期间腹腔压力变化对顺铂药代动力学的影响。
