Effect of the CYP2C19 genotype on the pharmacokinetics of icotinib in healthy male volunteers

Icotinib hydrochloride {4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline hydrochloride}, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), was designed for the treatment of non-small cell lung cancer (NSCLC). In the present study, we investigated the influence of the CYP2C19*2 and CYP2C19*3 alleles on the pharmacokinetics of icotinib in healthy Chinese volunteers. In a single-dose pharmacokinetic study, 12 healthy Chinese volunteers received an oral dose of 600 mg of icotinib. Plasma was sampled for up to 72 h post-dose, followed by quantification of icotinib by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS-MS). Five subjects genotyped as homozygous extensive metabolizers (CYP2C19*1/*1), 6 subjects genotyped as heterozygous extensive metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the research because of urticaria. The mean icotinib AUC(0-a) and C-max (14.56 +/- 5.31 h mg/L and 2.32 +/- 0.49 mu g/mL) in homozygous EMs was 1.56 and 1.41-fold lower than that in heterozygous EMs (22.7 +/- 6.11 and 3.28 +/- 0.48, P = 0.046 and 0.047). The mean CL/F (44.18 +/- 12.17 L/h) in homozygous EMs was 1.55-fold higher than that in heterozygous EMs (28.42 +/- 9.23 L/h, P = 0.013). The data showed that the pharmacokinetics of icotinib differ significantly between homozygous EMs and heterozygous EMs in CYP2C19.