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Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity.

AbstractPURPOSE:
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.
AuthorsCharles 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
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 26 Issue 7 Pg. 1119-27 (Mar 01 2008) ISSN: 1527-7755 [Electronic] United States
PMID18309947 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Quinazolines
  • Cytochrome P-450 Enzyme System
  • Erlotinib Hydrochloride
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • ErbB Receptors
Topics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters (genetics)
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Non-Small-Cell Lung (genetics, metabolism)
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System (genetics)
  • Diarrhea (chemically induced)
  • ErbB Receptors (antagonists & inhibitors, genetics)
  • Erlotinib Hydrochloride
  • Exanthema (chemically induced)
  • Female
  • Head and Neck Neoplasms (genetics, metabolism)
  • Humans
  • Lung Neoplasms (drug therapy, genetics)
  • Male
  • Middle Aged
  • Neoplasm Proteins (genetics)
  • Neoplasms, Squamous Cell (genetics, metabolism)
  • Ovarian Neoplasms (genetics, metabolism)
  • Pharmacogenetics
  • Polymorphism, Genetic
  • Prospective Studies
  • Protein Kinase Inhibitors (adverse effects, pharmacokinetics)
  • Quinazolines (adverse effects, pharmacokinetics)

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