In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship.

TLDR

Identifying a biologically active dose, rather than a maximum tolerated dose, has been a key challenge in developing molecularly targeted cancer therapies. The study aimed to define a pharmacokinetic/pharmacodynamic relationship in preclinical models to guide clinical dose selection. SU11248, a novel small‑molecule tyrosine‑kinase inhibitor targeting VEGF, PDGF, KIT, and FLT3 receptors, was evaluated in mouse xenografts, with target phosphorylation measured before and after treatment and correlated with plasma inhibitor levels. In mouse xenografts, SU11248 produced broad antitumor effects and dose‑dependent inhibition of VEGFR2 and PDGFRβ phosphorylation at plasma levels of 50–100 ng/ml, with sustained inhibition for 12 h of a 24‑h dosing interval, and the established PK/PD relationship has guided dosing regimens in human trials.

Abstract

One challenging aspect in the clinical development of molecularly targeted therapies, which represent a new and promising approach to treating cancers, has been the identification of a biologically active dose rather than a maximum tolerated dose. The goal of the present study was to identify a pharmacokinetic/pharmacodynamic relationship in preclinical models that could be used to help guide selection of a clinical dose. SU11248, a novel small molecule receptor tyrosine kinase inhibitor with direct antitumor as well as antiangiogenic activity via targeting the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), KIT, and FLT3 receptor tyrosine kinases, was used as the pharmacological agent in these studies. In mouse xenograft models, SU11248 exhibited broad and potent antitumor activity causing regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. To predict the target SU11248 exposure required to achieve antitumor activity in mouse xenograft models, we directly measured target phosphorylation in tumor xenografts before and after SU11248 treatment and correlated this with plasma inhibitor levels. In target modulation studies in vivo, SU11248 selectively inhibited Flk-1/KDR (VEGF receptor 2) and PDGF receptor beta phosphorylation (in a time- and dose-dependent manner) when plasma concentrations of inhibitor reached or exceeded 50-100 ng/ml. Similar results were obtained in a functional assay of VEGF-induced vascular permeability in vivo. Constant inhibition of VEGFR2 and PDGF receptor beta phosphorylation was not required for efficacy; at highly efficacious doses, inhibition was sustained for 12 h of a 24-h dosing interval. The pharmacokinetic/pharmacodynamic relationship established for SU11248 in these preclinical studies has aided in the design, selection, and evaluation of dosing regimens being tested in human trials.