Characterizing Gemcitabine Effects Administered as Single Agent or Combined with Carboplatin in Mice Pancreatic and Ovarian Cancer Xenografts: A Semimechanistic Pharmacokinetic/Pharmacodynamics Tumor Growth-Response Model

• DOI: 10.1124/jpet.116.237610
• Publication Date: 2016-12-28T02:00:28Z
• Authors: Maria Garcia-Crem...; Celine Pitou; Philip W. Iversen; Iñaki F. Troconiz
• Keywords: Carboplatin; Pharmacodynamics; Ovarian tumor

In this work, a semimechanistic tumor growth-response model for gemcitabine in pancreatic (administered as single agent) and ovarian (given agent combination with carboplatin) cancer mice was developed. Tumor profiles were obtained from nude mice, previously inoculated KP4, ASPC1, MIA PACA2, PANC1 (pancreas), A2780, or SKOV3×luc (ovarian) cell lines, then treated different dosing schedules of and/or carboplatin. Data fitted using the population approach Nonlinear Mixed Effect Models 7.2. addition to proliferation, progression both types incorporates carrying capacity representing metabolite pool DNA synthesis required growth. Analysis data groups revealed that exerted its effects by promoting apoptosis well decreasing compartment. Pharmacodynamic parameters cell-specific overall had similar range values between types. pancreas, linear used describe parameter 3.26 × 10-2 4.2 10-1 L/(mg d). cancer, apoptotic effect driven an EMAX efficacy/potency ratio 5.25-8.65 The contribution carboplatin lower than response incorporated inhibition capacity. developed consistent structure across lines two where is approved. Simulation-based evaluation diagnostics showed performed all experimental design scenarios, including dose, schedule, type.