title: Integrated pharmacogenetic prediction of irinotecan pharmacokinetics and toxicity in patients with advanced non-small cell lung cancer.
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.
authors.affiliation: Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea. jymama@ncc.re.kr
authors.forename: Ji-Youn
authors.initials: JY
authors.lastname: Han
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lim
authors.forename: Yong Hoon
authors.initials: YH
authors.lastname: Park
authors.forename: Sung Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Jin Soo
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000633:toxicity; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005838:Genotype; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D012737:Sex Factors; D016896:Treatment Outcome
chemical_list: C000715087:ABCC2 protein, human; D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D000089762:Multidrug Resistance-Associated Protein 2; D000077146:Irinotecan; D002166:Camptothecin