Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity

Charles M. Rudin, Wanqing Liu, Apurva Desai, Theodore Karrison, Xuemin Jiang, Linda Janisch, Soma Das, Jacqueline Ramirez, Balasubramanian Poonkuzhali, Erin Schuetz, Donna Lee Fackenthal, Peixian Chen, Deborah K. Armstrong, Julie R. Brahmer, Gini F. Fleming, Everett E. Vokes, Michael A. Carducci, Mark J. Ratain

Research output: Contribution to journalArticle

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. Patients 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 CYP3A5 were 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.

Original languageEnglish (US)
Pages (from-to)1119-1127
Number of pages9
JournalJournal of Clinical Oncology
Volume26
Issue number7
DOIs
StatePublished - Mar 1 2008

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Rudin, C. M., Liu, W., Desai, A., Karrison, T., Jiang, X., Janisch, L., Das, S., Ramirez, J., Poonkuzhali, B., Schuetz, E., Fackenthal, D. L., Chen, P., Armstrong, D. K., Brahmer, J. R., Fleming, G. F., Vokes, E. E., Carducci, M. A., & Ratain, M. J. (2008). Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. Journal of Clinical Oncology, 26(7), 1119-1127. https://doi.org/10.1200/JCO.2007.13.1128