Abstract
The aim of this study was to evaluate how CYP2C19 affects icotinib and metabolite' exposure, and to determine whether the exposure and EGFR genotype influences survival time, tumor metastasis and adverse drug reactions. 274 NSCLC patients who accepted 125 mg icotinib/t.i.d. were chosen from a phase III study. Blood samples were obtained in 672 nd (4th week) and 1,680 th hours (10th week), and plasma was used to quantify the concentration of icotinib and blood cells were sampled to check the genotypes. Clinical data were also collected at the same time, including EGFR genotypes. Plasma concentrations were assessed by HPLC-MS/MS and genotype by sequencing. All data were analyzed through SPSS 17.0 and SAS 9.2. CYP 2C19 genotypes affected bio-transformation from icotinib to M24 and M26, especially in poor-metabolisers. Higher icotinib concentrations (>1000 ng/mL) not only increased patient PFS and OS but also reduced tumor metastasis. Patients with mutant EGFR experienced a higher median PFS and OS (234 and 627 days), especially those with the 19del genotype demonstrating higher PR ratio. Patients who suffered grade II skin toxicity had a higher icotinib exposure than those with grade I skin toxicity or no adverse effects. Liver toxic reactions might occur in patients with greater M20 and M23 plasma concentrations. CYP2C19 polymorphisms significantly affect icotinib, M24 and M26 exposure. Patients with mutant EGFR genotype and higher icotinib concentration might have increased PFS and OS and lower tumor metastasis. Liver ADR events and serious skin effects might be respectively induced by greater M20, M23 and icotinib concentrations.
Highlights
Icotinib is an oral EGFR-TKI agent which is the first home-grown anticancer drug developed by Zhejiang Beta Pharma Inc. (Zhejiang, China) (Tan et al, 2012; Camidge, 2013)
The influenced factors described whether the progressive free survival time (PFS) or overall survival (OS), tumor size shrinkage rate, tumor metastasis, and adverse drug syndrome altered, the exposure of icotinib and its metabolites appeared individually different
Twenty-nine metabolites of icotinib were found in human plasma, urine, and feces, among which M20, M23, M24 and M26 counted around 80 % of the dosing amount in total (Liu et al, 2011)
Summary
Icotinib is an oral EGFR-TKI agent which is the first home-grown anticancer drug developed by Zhejiang Beta Pharma Inc. (Zhejiang, China) (Tan et al, 2012; Camidge, 2013). A paper published by Shi et al (2013) demonstrated that patients taking icotinib was with a longer progressive free survival time (PFS) than those taking gefitinib in a phase III study. The influence of CYP2C19 polymorphism in NSCLC patients was not further assessed, and some questions still keep puzzling: Whether changing of icotinib exposure would make influences on PD and therapeutic effect and have any relationship with toxicity are still confused. The aim of this study was to evaluate how CYP2C19 affects icotinib and metabolite’ exposure, and to determine whether the exposure and EGFR genotype influences survival time, tumor metastasis and adverse drug reactions. Higher icotinib concentrations (>1000 ng/mL) increased patient PFS and OS and reduced tumor metastasis. Patients with mutant EGFR genotype and higher icotinib concentration might have increased PFS and OS and lower tumor metastasis. Liver ADR events and serious skin effects might be respectively induced by greater M20, M23 and icotinib concentrations
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