PT  - JOURNAL ARTICLE
AU  - Maria Garcia-Cremades
AU  - Celine Pitou
AU  - Philip W. Iversen
AU  - Iñaki F. Troconiz
TI  - 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
AID  - 10.1124/jpet.116.237610
DP  - 2017 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 445--456
VI  - 360
IP  - 3
4099  - http://jpet.aspetjournals.org/content/360/3/445.short
4100  - http://jpet.aspetjournals.org/content/360/3/445.full
SO  - J Pharmacol Exp Ther2017 Mar 01; 360
AB  - In this work, a semimechanistic tumor growth-response model for gemcitabine in pancreatic (administered as single agent) and ovarian (given as single agent and in combination with carboplatin) cancer in mice was developed. Tumor profiles were obtained from nude mice, previously inoculated with KP4, ASPC1, MIA PACA2, PANC1 (pancreas), A2780, or SKOV3×luc (ovarian) cell lines, and then treated with different dosing schedules of gemcitabine and/or carboplatin. Data were fitted using the population approach with Nonlinear Mixed Effect Models 7.2. In addition to cell proliferation, the tumor progression model for both types of cancer incorporates a carrying capacity representing metabolite pool for DNA synthesis required to tumor growth. Analysis of data from the treated groups revealed that gemcitabine exerted its tumor effects by promoting apoptosis as well as decreasing the carrying capacity compartment. Pharmacodynamic parameters were cell-specific and overall had similar range values between cancer types. In pancreas, a linear model was used to describe both gemcitabine effects with parameter values between 3.26 × 10−2 and 4.2 × 10−1 L/(mg × d). In ovarian cancer, the apoptotic effect was driven by an EMAX model with an efficacy/potency ratio of 5.25–8.65 L/(mg × d). The contribution of carboplatin to tumor effects was lower than the response exerted by gemcitabine and was incorporated in the model as an inhibition of the carrying capacity. The model developed was consistent in its structure across different tumor cell lines and two tumor types where gemcitabine is approved. Simulation-based evaluation diagnostics showed that the model performed well in all experimental design scenarios, including dose, schedule, and tumor type.