TY - JOUR
T1 - Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity
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 K.
AU - Brahmer, Julie R.
AU - Fleming, Gini F.
AU - Vokes, Everett E.
AU - Carducci, Michael A.
AU - Ratain, Mark J.
PY - 2008/3/1
Y1 - 2008/3/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=41949140593&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41949140593&partnerID=8YFLogxK
U2 - 10.1200/JCO.2007.13.1128
DO - 10.1200/JCO.2007.13.1128
M3 - Article
C2 - 18309947
AN - SCOPUS:41949140593
SN - 0732-183X
VL - 26
SP - 1119
EP - 1127
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 7
ER -