title: Phase I clinical and pharmacological evaluation of the multi-tyrosine kinase inhibitor SU006668 by chronic oral dosing.
abstract: 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/m(2) b.i.d. Dose escalation was discontinued because the maximum tolerated dose was defined at 400 mg/m(2) b.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.
authors.affiliation: Istituto Oncologico della Svizzera Italiana, Via Ospedale, 6500 Bellinzona, Switzerland.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Sessa
authors.forename: Lucia
authors.initials: L
authors.lastname: Viganò
authors.forename: Giacomo
authors.initials: G
authors.lastname: Grasselli
authors.forename: Josè
authors.initials: J
authors.lastname: Trigo
authors.forename: Irene
authors.initials: I
authors.lastname: Marimon
authors.forename: Anna
authors.initials: A
authors.lastname: Lladò
authors.forename: Alberta
authors.initials: A
authors.lastname: Locatelli
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Ielmini
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsoni
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D000078183:Oxindoles; D011422:Propionates; D011485:Protein Binding; D011758:Pyrroles / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; C412603:orantinib