SU006668, an oral inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR), was administered in fed conditions to 24 patients with advanced solid cancer at 100, 200 and 300 mg/m2b.i.d. Dose escalation was discontinued because the maximum tolerated dose was defined at 400 mg/m2b.i.d in a concomitant trial. The drug was generally well tolerated although two patients presented possibly drug-related dose-limiting toxicities (pericardial effusion and thrombocytopenia). SU006668 had a non-linear pharmacokinetic profile characterized by AUC and Cmax decreasing from day 1 to day 28 in all patients at all tested doses; a lower apparent bioavailability on day 28 compared to day 1; and a significant concomitant increase of the urinary metabolites. These findings are in agreement with the presence of saturable absorption and metabolic induction. The peculiar pharmacokinetics and >99% protein binding discouraged further clinical development of oral SU006668 in humans.
Phase I clinical and pharmacological evaluation of the multi-tyrosine kinase inhibitor SU006668 by chronic oral dosing / C. Sessa, L. Viganò, G. Grasselli, J. Trigo, I. Marimon, A. Lladò, A. Locatelli, N. Ielmini, S. Marsoni, L. Gianni. - In: EUROPEAN JOURNAL OF CANCER. - ISSN 0959-8049. - 42:2(2006), pp. 171-178.
|Titolo:||Phase I clinical and pharmacological evaluation of the multi-tyrosine kinase inhibitor SU006668 by chronic oral dosing|
|Parole Chiave:||VEGF; tyrosine kinase inhibitor; SU006668; phase I; trial|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||2006|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.ejca.2005.09.033|
|Appare nelle tipologie:||01 - Articolo su periodico|