title: Pharmacogenetics of telatinib, a VEGFR-2 and VEGFR-3 tyrosine kinase inhibitor, used in patients with solid tumors.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Centre, K1-P, P.O Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Neeltje
authors.initials: N
authors.lastname: Steeghs
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.forename: Judith
authors.initials: J
authors.lastname: Wessels
authors.forename: Ferry A L M
authors.initials: FA
authors.lastname: Eskens
authors.forename: Natasja
authors.initials: N
authors.lastname: de Bont
authors.forename: Johan W R
authors.initials: JW
authors.lastname: Nortier
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011725:Pyridines; C533371:telatinib; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3