RT Journal Article
T1 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
A1 García-Cremades Mira, María
A1 Pitou, Celine
A1 Iversen, Philip W.
A1 Fernández De Troconiz, Iñaki
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.
PB American Society for Pharmacology and Experimental Therapeutics
SN 0022-3565
YR 2016
FD 2016-12-27
LK https://hdl.handle.net/20.500.14352/100756
UL https://hdl.handle.net/20.500.14352/100756
LA eng
NO Garcia-Cremades, Maria, et al. «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». Journal of Pharmacology and Experimental Therapeutics, vol. 360, n.o 3, marzo de 2017, pp. 445-56. DOI.org (Crossref), https://doi.org/10.1124/jpet.116.237610.
NO Eli Lilly and Company
NO DDMORE project
DS Docta Complutense
RD 21 abr 2025