Department of Clinical Oncology, Leiden University Medical Centre, K1-P, P.O Box 9600, 2300 RC, Leiden, The Netherlands.
Invest New Drugs. 2011 Feb;29(1):137-43. doi: 10.1007/s10637-009-9347-0. Epub 2009 Nov 19.
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.
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.
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.
Our pharmacogenetic analysis could not reveal a correlation between relevant gene polymorphisms and clinical and pharmacokinetic observations of telatinib.
替拉替尼是一种具有口服活性的小分子激酶抑制剂，可抑制激酶插入结构域受体（KDR；VEGFR-2）和胎肝激酶 4（FLT4；VEGFR-3）。本研究旨在确定编码转运蛋白的基因中单核苷酸多态性（SNP）与药代动力学参数之间的关系，以阐明药物暴露的显著个体间差异。此外，还探讨了替拉替尼的靶受体多态性与毒性之间的潜在关系。
分析了 33 名参加替拉替尼 I 期剂量递增研究的患者的血样。为了与剂量归一化 AUC（0-12）相关，选择了 ABCB1（ABCB1）、ABCC1 和 ABCG2 作为候选基因。为了与替拉替尼毒性相关，选择了药物靶点基因 KDR 和 FLT4 作为候选基因。
未观察到剂量归一化 AUC（0-12）与药物转运蛋白蛋白多态性之间存在关联。此外，毒性与 KDR 或 FLT4 基因型或单倍型之间也没有关联。
我们的药物遗传学分析未能揭示相关基因多态性与替拉替尼的临床和药代动力学观察之间的相关性。
