title: 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.
abstract: 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 × 10-2and 4.2 × 10-1L/(mg × d). In ovarian cancer, the apoptotic effect was driven by an EMAXmodel 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.
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, and Navarra Institute for Health Research (IdiSNA), University of Navarra, Pamplona, Spain (M.G.-C., I.F.T.); Global Pharmacokinetic/Pharmacodynamics and Pharmacometrics, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (C.P.); and Lilly Research laboratories, Eli Lilly and Company, Indianapolis, Indiana (P.W.I.).
authors.forename: Maria
authors.initials: M
authors.lastname: Garcia-Cremades
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, and Navarra Institute for Health Research (IdiSNA), University of Navarra, Pamplona, Spain (M.G.-C., I.F.T.); Global Pharmacokinetic/Pharmacodynamics and Pharmacometrics, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (C.P.); and Lilly Research laboratories, Eli Lilly and Company, Indianapolis, Indiana (P.W.I.).
authors.forename: Celine
authors.initials: C
authors.lastname: Pitou
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, and Navarra Institute for Health Research (IdiSNA), University of Navarra, Pamplona, Spain (M.G.-C., I.F.T.); Global Pharmacokinetic/Pharmacodynamics and Pharmacometrics, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (C.P.); and Lilly Research laboratories, Eli Lilly and Company, Indianapolis, Indiana (P.W.I.).
authors.forename: Philip W
authors.initials: PW
authors.lastname: Iversen
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, and Navarra Institute for Health Research (IdiSNA), University of Navarra, Pamplona, Spain (M.G.-C., I.F.T.); Global Pharmacokinetic/Pharmacodynamics and Pharmacometrics, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (C.P.); and Lilly Research laboratories, Eli Lilly and Company, Indianapolis, Indiana (P.W.I.) itroconiz@unav.es.
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Troconiz
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D064593:Heterografts / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D016190:Carboplatin; D000093542:Gemcitabine