Integrated pharmacogenetic prediction of irinotecan pharmacokinetics and toxicity in patients with advanced non-small cell lung cancer.

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Han JY, Lim HS, Park YH, Lee SY, Lee JS

Integrated pharmacogenetic prediction of irinotecan pharmacokinetics and toxicity in patients with advanced non-small cell lung cancer.

Lung Cancer. 2009 Jan;63(1):115-20. doi: 10.1016/j.lungcan.2007.12.003. Epub 2008 Jan 24.

PubMed ID

18221820 [ View in PubMed

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Abstract

To define an integrated pharmacogenetic model for predicting irinotecan pharmacokinetic (PK) and severe toxicity, we evaluated multivariate analysis using 15 polymorphisms within seven genes with putative influence on metabolism and transport of irinotecan. A total of 107 NSCLC patients treated with irinotecan were evaluated for PK and genotyped for the UGT1A1*6, UGT1A1*28, UGT1A9*22, ABCB11236C>T, 2677G>T/A, 3435C>T, ABCC2-24C>T, 1249G>A, 3972C>T, ABCG234G>A, 421C>A, and SLCO1B1 -11187G>A, 388A>G, and 521T>C, and CYP3A5*3 polymorphisms. Multivariate linear and logistic regression analyses including genotypes and clinicopathologic factors were performed. SN-38 AUC was significantly correlated with ANCs (r=-0.3, p=0.009) and grade 4 neutropenia (p=0.01). The UGT1A1*6/*6, UGT1A9*1/*1 or *1/*22, and SLCO1B1 521TC or CC genotypes, and female-gender were predictive for higher AUC(SN-38) in multivariate analysis. Among them, SLCO1B1 521TC or CC and UGT1A1*6/*6 genotypes were independently predictive for grade 4 neutropenia in multivariate analysis (OR=3.8 and 7.4, respectively). Although no significant association was observed between PK parameters and grade 3 diarrhea, UGT1A9*1/*1, ABCC23972CC, and ABCG234GA or AA genotypes were independently predictive for grade 3 diarrhea in multivariate analysis (OR=6.3, 5.6, and 5.1, respectively). Patient selection based on integrated pharmacogenetic model would be helpful for predicting irinotecan-PK and severe toxicities in NSCLC patients.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Irinotecan	Canalicular multispecific organic anion transporter 1	Protein	Humans	Unknown	Substrate	Details
Irinotecan	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details