Determinants of gefitinib pharmacokinetics in healthy Chinese male subjects: A pharmacogenomic study of cytochrome p450 enzymes and transporters

• Published in: Journal of clinical pharmacy and therapeutics Vol. 45; no. 5; pp. 1159 - 1167
• Main Authors: Wan, Zirui, Guo, Lifang, Li, Pengfei, Zhao, Zhixia, Xu, Benshan, Ren, Lulu, Yan, Yan, Liu, He, Zhang, Yiwen, Liu, Lihong
• Format: Journal Article
• Language: English
• Published: Oxford John Wiley & Sons, Inc 01.10.2020
• Subjects: Alleles; Cytochrome; Cytochrome P450; Enzymes; Epidermal growth factor; Gefitinib; Gene polymorphism; Inhibitor drugs; Liquid chromatography; Mass spectroscopy; Pharmacodynamics; Pharmacogenomics; Pharmacokinetics; Polymorphism; Protein-tyrosine kinase receptors; Single‐nucleotide polymorphism; Toxicity
• ISSN: 0269-4727; 1365-2710; 1365-2710
• DOI: 10.1111/jcpt.13168

What is known and objective Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, exhibited a wide interindividual variability in pharmacokinetics. In the present study, we aimed to evaluate the impact of single‐nucleotide polymorphisms in the metabolizing enzymes and transporters on gefitinib disposition in healthy Chinese subjects. Methods Fourteen single‐nucleotide polymorphisms, including polymorphisms of ATP‐binding cassette (ABC) transporters and cytochrome P450 enzymes, were genotyped by Sanger sequencing, and the concentration of gefitinib was measured by ultrafast liquid chromatography‐tandem mass spectrometry. The association between the pharmacokinetic parameters (peak plasma concentration [Cmax], time to reach Cmax, plasma half‐life, area under the concentration‐time curve from 0 to 168 hours [AUC(0‐168h)], AUC(0‐∞) and plasma clearance [CL/F]) and genotypes was evaluated using unpaired t test or Mann‐Whitney U test. A stepwise multiple linear regression analysis was applied to assess the relationships between multiple factors and gefitinib pharmacokinetics. Thirty‐nine healthy Chinese male subjects were enrolled in the pharmacokinetic study. Results and discussion Subjects carrying an ABCG2 A allele (c.421CA + c.421AA genotypes) exhibited 33 and 37% increases in the mean gefitinib AUC(0‐168h) and AUC(0‐∞) values (P < .05), respectively, compared to that of subjects carrying wild‐type ABCG2 (c.421CC). Additionally, the mean CL/F of the c.421A allele carriers was 32% less than that of the c.421CC carriers (P < .05). No associations were found between polymorphisms in other metabolic enzymes or ABC transporters and gefitinib pharmacokinetics. What is new and conclusion Our results suggested that a single‐nucleotide polymorphism in ABCG2 (c.421C>A) significantly affected the pharmacokinetics of gefitinib. Further studies are required to evaluate the effects of single‐nucleotide polymorphism on the pharmacokinetics, pharmacodynamics and toxicity of gefitinib. Gefitinib, an inhibitor of epidermal growth factor receptor tyrosine kinase, was widely used in the treatment for patients with advanced platinum‐resistant non‐small‐cell lung cancer (NSCLC). Single nucleotide polymorphisms have been shown to alter gefitinib disposition, and we evaluated SNPs in the cytochrome p450 enzymes and transporters involved in the metabolism and transport of gefitinib. Our data suggest that ABCG2 c.421C>A influence pharmacokinetics of gefitinib significantly in Chinese health subjects.