title: Preclinical Modeling of Tumor Growth and Angiogenesis Inhibition to Describe Pazopanib Clinical Effects in Renal Cell Carcinoma.
abstract: The objective was to leverage tumor size data from preclinical experiments to propose a model of tumor growth and angiogenesis inhibition for the analysis of pazopanib efficacy in renal cell carcinoma (RCC) patients. We analyzed tumor data in mice with RCC CAKI-2 cell line treated with pazopanib. Clinical tumor size data obtained in a subset of patients with RCC were also analyzed. A model accounting for the processes of tumor growth, angiogenesis, and drug effect was developed. The final tumor model was composed of two variables: the tumor and its vasculature. Our results show that, both in mice and in humans, pazopanib exhibits a dual mechanism of action, and parameter estimation values highlight the inherent difference between mice and humans on the time scale of tumor size response. We developed a semimechanistic tumor growth inhibition model that takes into account tumor angiogenesis in order to describe the effects of pazopanib in mice. Analyzing rich preclinical data with a semimechanistic model may be a relevant approach to facilitate the description of sparse clinical longitudinal tumor size data and to provide insights for the understanding of the drug mechanisms of action in patients.
authors.affiliation: Inria, project team NuMed Ecole Normale Supérieure de Lyon, Lyon France.
authors.forename: A
authors.initials: A
authors.lastname: Ouerdani
authors.affiliation: GlaxoSmithKline, Clinical Pharmacology Modeling & Simulation Research Triangle Park North Carolina USA.
authors.forename: H
authors.initials: H
authors.lastname: Struemper
authors.affiliation: GlaxoSmithKline, Clinical Pharmacology Modeling & Simulation Research Triangle Park North Carolina USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Suttle
authors.affiliation: GlaxoSmithKline, Clinical Pharmacology Modeling & Simulation Research Triangle Park North Carolina USA.
authors.forename: D
authors.initials: D
authors.lastname: Ouellet
authors.affiliation: Inria, project team NuMed Ecole Normale Supérieure de Lyon, Lyon France.
authors.forename: B
authors.initials: B
authors.lastname: Ribba