Pharmacogenetic influence of OATP1B1 variants *1b and *15 on irinotecan disposition in Asian and Caucasian cancer patients

Abstract

13069 Background: The objective of this study was to evaluate the impact of OATP1B1 (SLCO1B1; OATP-C) functional variants on the disposition of irinotecan in Asian and Caucasian cancer patients. Methods: Irinotecan pharmacokinetic parameters and OATP1B1*1a, *1b, *5 and *15 genotyping data were obtained from Asian (N=71) and Caucasian (N=30) cancer patients receiving the drug as a 90-minute i.v. infusion. Genotypic-phenotypic correlations were assessed in cancer patients from each ethnic group. Results: The *1a/*1a genotype and the *15/*15 diplotype were absent in Caucasian cancer patients but present in Asians (*1a/*1a, N=6; *15/*15, N=1). Statistically insignificant differences were observed between patients carrying *1a/*1b and *1b/*1b genotypes and also between *1b/*15, *15/*15 and *15/*15 diplotypes. Compared to wild-type patients (N=6), total irinotecan clearance normalized by BSA was 2- and 3-fold lower in Asian patients carrying at least one *1b (*1a/*1b + *1b/*1b; N=54; P=0.055) and one *15 (*1b/*15 + *5/*15 + *15/*15; N=11; P=0.001) allele, respectively. Significant differences were also present between Asian patients carrying the *15 diplotype and wild-type patients with regard to exposure levels (Cmax/dose/BSA) to irinotecan (P=0.007), SN-38 (P=0.009) and SN-38G (P=0.004) as well as REC (P=0.005) and REG (0.001). The REG was 5-fold (P=0.022) and 27-fold (P=0.001) lower in Asian cancer patients carrying at least one *1b allele and at least one *15 haplotype, respectively, when compared with wild-type patients. No significant differences in pharmacokinetic parameters were found when comparing Caucasian cancer patients carrying at least one *1b allele and those carrying at least one *15 allele (P>0.05). Conclusions: The genotype and diplotype frequencies of the studied OATP1B1 variants were ethnically dependent, and OATP1B1 genotype status accounts, at least in part, for the observed differences in irinotecan disposition in Asian cancer patients. The lack of significant influence of OATP1B1 variants on irinotecan disposition in Caucasian cancer patients is not clear but may have resulted from the small patient population. No significant financial relationships to disclose.