Pharmacogenetics of telatinib, a VEGFR-2 and VEGFR-3 tyrosine kinase inhibitor, used in patients with solid tumors
Summary: Purpose Telatinib is an orally active small-molecule tyrosine kinase inhibitor of kinase insert domain receptor (KDR; VEGFR-2) and fms-related tyrosine kinase 4 (FLT4; VEGFR-3). This study aims at the identification of relationships between single nucleotide polymorphisms (SNPs) in genes encoding for transporter proteins and pharmacokinetic parameters in order to clarify the significant interpatient variability in drug exposure. In addition, the potential relationship between target receptor polymorphisms and toxicity of telatinib is explored. Methods Blood samples from 33 patients enrolled in a phase I dose-escalation study of telatinib were analyzed. For correlation with dose normalized AUC(0-12), ATP-binding cassette (ABC) B1 (ABCB1), ABCC1, and ABCG2 were the genes selected. For correlation with telatinib toxicity, selected genes were the drug target genes KDR and FLT4. Results No association between dose normalized AUC(0-12) and drug transporter protein polymorphisms was observed. In addition, no association between toxicity and KDR or FLT4 genotype or haplotype was seen. Conclusions Our pharmacogenetic analysis could not reveal a correlation between relevant gene polymorphisms and clinical and pharmacokinetic observations of telatinib.
|Keywords||ABC transporter, ABC transporter A1, ABC transporter C1, adrenal cancer, adult, aged, area under the curve, article, bile duct, breast cancer resistance protein, cancer chemotherapy, cancer classification, carcinoma, clinical article, colorectal cancer, controlled study, disease severity, dosage schedule comparison, dose response, drug dose escalation, drug exposure, esophagus cancer, female, gene frequency, gene targeting, genetic association, genetic code, genetic linkage, genetic selection, haplotype, human, hypertension, male, melanoma, multicenter study, multiple cycle treatment, ovary cancer, pharmacogenetics;, phase 1 clinical trial, priority journal, single nucleotide polymorphism, soft tissue sarcoma, solid tumor, telatinib, time to maximum plasma concentration, unclassified drug, vasculotropin receptor 2, vasculotropin receptor 3|
|Persistent URL||dx.doi.org/10.1007/s10637-009-9347-0, hdl.handle.net/1765/23522|
|Journal||Investigational New Drugs: the journal of new anti-cancer agents|
Steeghs, N, Gelderblom, A.J, Wessels, J.A.M, Eskens, F.A.L.M, de Bont, N, Nortier, J.W, & Guchelaar, H.J. (2011). Pharmacogenetics of telatinib, a VEGFR-2 and VEGFR-3 tyrosine kinase inhibitor, used in patients with solid tumors. Investigational New Drugs: the journal of new anti-cancer agents, 29(1), 137–143. doi:10.1007/s10637-009-9347-0