Association analysis of SNPs present in plasma with adverse events and population pharmacokinetics in Chinese sunitinib treated patients with renal cell carcinoma

BACKGROUND: Sunitinib is a tyrosine kinase inhibitor with effective therapeutic outcomes in patients with renal-cell carcinoma. The study were to analyze the association of single-nucleotide polymorphisms present in cell-free DNA and pharmacokinetics with sunitinib treatment-emergent adverse events in Chinese patients with renal-cell carcinoma. MATERIALS AND METHODS: We genotyped 8 keys SNPs in 6 candidate genes. The plasma concentrations of sunitinib and N-desethyl sunitinib were measured using a high performance liquid chromatography-tandam mass spectrometry method. Correlations between the single-nucleotide polymorphisms and adverse events were investigated by univariate and multivariate logistic regression and we quantitatively evaluated the effect of single-nucleotide polymorphisms on the pharmacokinetics of sunitinib by using a population PK model. RESULTS: Necessary dose reductions of sunitinib were significantly correlated with SNP rs1933437 in FLT3. A higher severity of AEs were collected with SNP rs2032582 in ABCB1 and rs1800812 in PDGFRα. Thrombocytopenia was collected with rs1800812 in PDGFRα. Our study provides a population PK model of sunitinib with the ABCB1 genotype as a predictive covariate for apparent oral clearance. CONCLUSIONS: Our study preliminarily confirmed the hypothesis that the pharmacokinetics of sunitinib is affected by the SNPs of enzyme in Chinese renal-cell carcinoma patients, and this affects the different distribution and severity of adverse events of sunitinib.