Effect of genetic polymorphisms on the pharmacokinetics of gefitinib in healthy Chinese volunteers

Abstract

1. Gefitinib is the first-generation drug of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) metabolised by the cytochrome P450 and transported by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). In the present study, the pharmacokinetics of gefitinib in healthy Chinese volunteers was investigated and the effect of genetic polymorphisms on its variability was evaluted.

2. Forty-five healthy volunteers were administered a single dose of gefitinib and the blood samples were used for quantifying the concentration of gefitinib and genotyping fifteen single-nucleotide polymorphisms of cytochrome P450 enzymes (CYP3A4, CYP3A5, CYP2D6, CYP2C9 and CYP2C19) and drug transporters (ABCB1 and ABCG2).

3. CYP3A5*3 (rs776746) polymorphism showed a significant influence, with higher gefitinib AUC_0-t in carrier of CC genotype than in CT/TT genotype (BH-adjusted p value <0.05). For CYP2C9*3 (rs1057910), significant differences in pharmacokinetics of gefitinib were detected between carriers of AA and AC genotypes, with higher AUC_0-t, AUC_0-∞ and C_max in carrier of AC genotype than in AA gen-otype (BH-adjusted p value <0.05). No associations were found between SNPs in CYP3A4, CYP2D6, CYP2C19, ABCB1, ABCG2 and the pharmacokinetics of gefitinib.

4. The SNPs in CYP3A5*3 (rs776746) and CYP2C9*3 (rs1057910) were found to be associated with altered gefitinib pharmacokinetics in healthy Chinese volunteers.

Keywords:

• Gefitinib
• Genetic polymorphism
• Pharmacokinetics
• CYP3A5
• CYP2C9

Acknowledgments

The authors are grateful to the volunteers who participated in this study. This study was supported by Furen Pharmaceutical Company Limited, Public Welfare Application Research Project of Huzhou Technology Plan and Youth Talent Program of Huzhou Central Hospital.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was funded by Furen Pharmaceutical Company Limited, Henan, China, Public Welfare Application Research Project of Huzhou Technology Plan (grant number 2021GZ71) and Youth Talent Program of Huzhou Central Hospital(grant number 2020YC12).