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 Kay Armstrong, Julie 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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Pharmacogenetics
Epidermal Growth Factor Receptor
Pharmacokinetics
Exanthema
Cytochrome P-450 CYP3A
Head and Neck Neoplasms
Diarrhea
Logistic Models
Erlotinib Hydrochloride
Non-Small Cell Lung Carcinoma
Ovarian Neoplasms
Protein-Tyrosine Kinases
Introns
Area Under Curve
Appointments and Schedules
Alleles
Prospective Studies
Skin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Rudin, C. M., Liu, W., Desai, A., Karrison, T., Jiang, X., Janisch, L., ... 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

Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. / Rudin, Charles M.; Liu, Wanqing; Desai, Apurva; Karrison, Theodore; Jiang, Xuemin; Janisch, Linda; Das, Soma; Ramirez, Jacqueline; Poonkuzhali, Balasubramanian; Schuetz, Erin; Fackenthal, Donna Lee; Chen, Peixian; Armstrong, Deborah Kay; Brahmer, Julie; Fleming, Gini F.; Vokes, Everett E.; Carducci, Michael A; Ratain, Mark J.

In: Journal of Clinical Oncology, Vol. 26, No. 7, 01.03.2008, p. 1119-1127.

Research output: Contribution to journalArticle

Rudin, CM, Liu, W, Desai, A, Karrison, T, Jiang, X, Janisch, L, Das, S, Ramirez, J, Poonkuzhali, B, Schuetz, E, Fackenthal, DL, Chen, P, Armstrong, DK, Brahmer, J, Fleming, GF, Vokes, EE, Carducci, MA & Ratain, MJ 2008, 'Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity', Journal of Clinical Oncology, vol. 26, no. 7, pp. 1119-1127. https://doi.org/10.1200/JCO.2007.13.1128
Rudin CM, Liu W, Desai A, Karrison T, Jiang X, Janisch L et al. Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. Journal of Clinical Oncology. 2008 Mar 1;26(7):1119-1127. https://doi.org/10.1200/JCO.2007.13.1128
Rudin, Charles M. ; Liu, Wanqing ; Desai, Apurva ; Karrison, Theodore ; Jiang, Xuemin ; Janisch, Linda ; Das, Soma ; Ramirez, Jacqueline ; Poonkuzhali, Balasubramanian ; Schuetz, Erin ; Fackenthal, Donna Lee ; Chen, Peixian ; Armstrong, Deborah Kay ; Brahmer, Julie ; Fleming, Gini F. ; Vokes, Everett E. ; Carducci, Michael A ; Ratain, Mark J. / Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. In: Journal of Clinical Oncology. 2008 ; Vol. 26, No. 7. pp. 1119-1127.
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AU - Rudin, Charles M.

AU - Liu, Wanqing

AU - Desai, Apurva

AU - Karrison, Theodore

AU - Jiang, Xuemin

AU - Janisch, Linda

AU - Das, Soma

AU - Ramirez, Jacqueline

AU - Poonkuzhali, Balasubramanian

AU - Schuetz, Erin

AU - Fackenthal, Donna Lee

AU - Chen, Peixian

AU - Armstrong, Deborah Kay

AU - Brahmer, Julie

AU - Fleming, Gini F.

AU - Vokes, Everett E.

AU - Carducci, Michael A

AU - Ratain, Mark J.

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N2 - 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.

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