Pharmacokinetic/pharmacodynamic modeling of etoposide tumor growth inhibitory effect in Walker-256 tumor-bearing rat model using free intratumoral drug concentrations

详细信息    查看全文

• 作者：Maiara Cá ; ssia Pigatto^a ; ^b ; ^c ; Renatha Menti Roman^c ; Letizia Carrara^d ; André ; ia Buffon^a ; ^c ; Paolo Magni^d ; Teresa Dalla Costa^a ; ^c ; ^{dalla.costa@ufrgs.br}
• 关键词：W256 ; Walker-256 ; HPLC-UV ; high pressure liquid chromatography-ultraviolet ; PK/PD ; pharmacokinetic/pharmacodynamic ; popPK ; population pharmacokinetic ; TGI ; Tumor Growth Inhibition ; NAD ; Naï ; ve Average Data ; SAEM ; stochastic approximation expectation maximization ; GOF ; goodness-of-fit ; VPC ; visual predictive check ; AUC ; area under the curve
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：97
• 期：Complete
• 页码：70-78
• 全文大小：799 K
• 卷排序：97

文摘

The purpose of this study was to establish a population pharmacokinetic/pharmacodynamic (PK/PD) model linking etoposide free tumor and total plasma concentrations to the inhibition of solid tumor growth in rats. Walker-256 tumor cells were inoculated subcutaneously in the right flank of Wistar rats, which were randomly divided in control and two treated groups that received etoposide 5 or 10 mg/kg i.v. bolus every day for 8 and 4 days, respectively, and tumor volume was monitored daily for 30 days. The plasma and intratumoral concentrations-time profiles were obtained from a previous study and were modeled by a four-compartment population pharmacokinetic (popPK) model. PK/PD analysis was conducted using MONOLIX v.4.3.3 on average data and by mean of a nonlinear mixed-effect model. PK/PD data were analyzed using a modification of Simeoni Tumor Growth Inhibition (TGI) model by introduction of an Emax function to take into account the concentration dependency of k2variable parameter (variable potency). The Simeoni TGI-Emax model was capable to fit schedule-dependent antitumor effects using the tumor growth curves from the control and two different administered schedules. The PK/PD model was capable of describing the tumor growth inhibition using total plasma or free tumor concentrations, resulting in higher k2max (maximal potency) for free concentrations (25.8 mL·μg− 1·day− 1 - intratumoral vs. 12.6 mL·μg− 1·day− 1 total plasma). These findings indicate that the plasma concentration may not be a good surrogate for pharmacologically active free tumor concentrations, emphasizing the importance of knowing drug tumor penetration to choose the best antitumor therapy.