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

Summary

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.

Introduction

Irinotecan is characterized by a wide inter-patient variability in pharmacokinetics (PK) and subsequent pharmacologic effects and toxicity [1]. It is metabolized by carboxylesterase to form an active metabolite, SN-38, which is further conjugated and detoxified by uridine diphosphate glucuronosyltransferase 1A (UGT1A) to yield SN-38 glucuronide (SN-38G) [2], [3]. Irinotecan is also subject to oxidation by the cytochrome P450 3A (CYP3A) family, which catalyzes the formation of inactive metabolites such as APC and NPC [4], [5]. NPC may be further metabolized into SN-38 by carboxylesterase [6]. Beside the hepatic metabolizing enzymes, drug transporters have been implicated in the disposition of irinotecan and its metabolites, as well. The ATP-binding cassette (ABC) transporters such as, ABCC2 (cMOAT, MRP2) and a lesser extent, ABCB1 (MDR1) and ABCG2 (BCRP), present on the bile canalicular membrane, are responsible for facilitating biliary excretion of irinotecan and its metabolites [7], [8], [9]. In addition, the organic anion transporting polypeptides (OATPs) are expressed on the basolateral domain of hepatocytes and facilitate the uptake of drugs before their elimination into bile. Among several isoforms, the OATP1B1 is supposed to be involved in the hepatic transport of SN-38 [10].

Previously we conducted exploratory irinotecan pharmacogenetic analyses using several polymorphisms in UGT1A1, UGT1A9, ABCB1, ABCC2, ABCG2, and SLCO1B1 genes, and evaluated their significance in NSCLC patients separately [11], [12], [13]. However, irinotecan pharmacology is complex and may be dependent on the interplay of metabolizing enzymes and transporters. Moreover, altered function caused by single gene variation can be obscured by the compensatory activity of other enzymes and transporters. Therefore, metabolizing enzymes, transporters, and other potential regulatory factors should be viewed and evaluated as an integrated system rather than single component for the accurate prediction of irinotecan-PK and toxicity.

To define an integrated pharmacogenetic model for predicting irinotecan-PK and severe toxicities in NSCLC patients treated with irinotecan plus cisplatin chemotherapy, we conducted this multivariate analysis using 15 polymorphisms within seven genes with putative influence on metabolism and transport of irinotecan and its metabolites as well as patients’ clinicopathologic factors.