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

Abstract

PURPOSE:

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.

METHODS:

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).

RESULTS:

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metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the research because of urticaria.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-∞) and C(max) (14.56 ±5.31 h mg/L and 2.32 ± 0.49 μg/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).

CONCLUSIONS:

The data showed that the pharmacokinetics of icotinib differ significantly between homozygous EMs and heterozygous EMs in CYP2C19.

• Authors: Can-Jun Ruan, Dong-Yang Liu, Ji Jiang, Pei Hu
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 68 Issue 12 Pg. 1677-80 (Dec 2012) ISSN: 1432-1041 [Electronic] Germany
• PMID: 22585284 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Crown Ethers
• Protein Kinase Inhibitors
• Quinazolines
• icotinib
• Aryl Hydrocarbon Hydroxylases
• CYP2C19 protein, human
• Cytochrome P-450 CYP2C19

Topics

• Adult
• Alleles
• Antineoplastic Agents (blood, pharmacokinetics)
• Area Under Curve
• Aryl Hydrocarbon Hydroxylases (genetics)
• Crown Ethers (blood, pharmacokinetics)
• Cytochrome P-450 CYP2C19
• Genotype
• Humans
• Male
• Protein Kinase Inhibitors (blood, pharmacokinetics)
• Quinazolines (blood, pharmacokinetics)