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

J Clin Pharm Ther. 2020 Oct;45(5):1159-1167. doi: 10.1111/jcpt.13168. Epub 2020 Jun 20.

Abstract

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.

Keywords: Single-nucleotide polymorphism; gefitinib; pharmacokinetics.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics*
  • ATP-Binding Cassette Transporters / genetics
  • Adult
  • Area Under Curve
  • Asian People / genetics
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 Enzyme System / genetics
  • Gefitinib / pharmacokinetics*
  • Genotype
  • Half-Life
  • Humans
  • Male
  • Neoplasm Proteins / genetics*
  • Pharmacogenomic Testing
  • Polymorphism, Single Nucleotide
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Tandem Mass Spectrometry
  • Young Adult

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Cytochrome P-450 Enzyme System
  • Gefitinib