Pharmacogenomic and Pharmacokinetic Determinants of Erlotinib Toxicity

Abstract

Purpose-To assess the pharmacogenomic and pharmacokinetic determinants of skin rash and diarrhea, the two primary dose-limiting toxicities of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTAlthough all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptPatients and Methods-A prospective clinical study of 80 patients with non-small-cell lung cancer, head and neck cancer, and ovarian cancer was performed. Detailed pharmacokinetics and toxicity of erlotinib were assessed. Polymorphic loci in EGFR, ABCG2, CYP3A4, and CYP3A5were genotyped, and their effects on pharmacokinetics and toxicities were evaluated.Results-A novel diplotype of two polymorphic loci in the ABCG2 promoter involving −15622C/T and 1143C/T was identified, with alleles conferring lower ABCG2 levels associated with higher erlotinib pharmacokinetic parameters, including area under the curve (P = .019) and maximum concentration (P = .006). Variability in skin rash was best explained by a multivariate logistic regression model incorporating the trough erlotinib plasma concentration (P = .034) and the EGFR intron 1 polymorphism (P = .044). Variability in diarrhea was associated with the two linked polymorphisms in the EGFR promoter (P < .01), but not with erlotinib concentration.Conclusion-Although exploratory in nature, this combined pharmacogenomic and pharmacokinetic model helps to define and differentiate the primary determinants of skin and gastrointestinal toxicity of erlotinib. The findings may be of use both in designing trials targeting a particular severity of rash and in considering dose and schedule modifications in patients experiencing dose-limiting toxicities of erlotinib or similarly targeted agents. Further studies of the relationship between germline polymorphisms in EGFR and the toxicity and efficacy of EGFR inhibitors are warranted.

Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population

“…In addition, this SNP has been associated with increased plasma exposure to erlotinib [41] and higher risk for the development of gefitinib [42] and sunitinib [43] induced toxicity/ adverse events. The fact that an association between the rs2622604 genotype and statin kinetics was identified in this work is of particular importance, as up to now most of the BCRP-related pharmacogenetic research in this class of drugs focuses on the effects of the c.421C>A polymorphism.…”

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

“…The multidrug transporter ABCG2 was shown to be active in removing gefitinib from cells (Elkind et al, 2005). In published reports, ABCG2 polymorphisms have been identified as being associated with increased EGFR TKI concentrations, toxicity or both, in patients treated with gefitinib and erlotinib (Cusatis et al, 2006;Li et al, 2007;Rudin et al, 2008).…”

Algorithms for Management of Patients With Adverse Events on Therapy With Tyrosine Kinase Inhibitors Egfr

“…Несмотря на ограниченные данные по фотосенсиби-лизирующему действию ИТК-EGFR, пациентам рекомен-дуется прикрывать незащищенные участки кожи и использовать солнцезащитные средства SPF 30 UVА/UVB, не образующие непроницаемую пленку, особенно при сильном солнечном воздействии [42][43][44]. В качестве средств личной гигиены, рекомендуется использовать водные смягчающие средства и заменители мыла -они в меньшей степени подсушивают кожу, чем обычное мыло; рекомендуется использовать шампуни, снижающие риск фолликулита головы, например, кетоконазол, бетадин.…”

“…В исследованиях III фазы у 25-95% пациентов наблю-дались НЯ любой степени и 1-14% -НЯ ≥3 степени (табл. 9) [11][12][13][14][15][16][17][18][19][20][39][40][41][42][43][44][45][46][47][48].…”