Effect of OATPIBI (SLCOIBI) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers

Background. Pitavastatin is a potent, newly developed 3-hydroxy-3-methylglutaryl- coenzyme A reductase inhibitor for the treatment of hyperlipidemia. We characterized the effects of organic anion transporting polypeptide 1B1 (OATP1B1) alleles *1a, *1b, and *15 on the pharmacokinetics of pitavastatin. Methods: Twenty-four healthy Korean volunteers who had-previously participated in a pharmacokinetic study of pitavastatin (single oral dose, 1-8 mg) were further investigated. Subjects were grouped according to OATP1B1 genotype. Dose-normalized area under the plasma concentration-time curve (AUC) and peak plasma concentration C-max values were analyzed, because different dosages were administered to subjects, whereas the pharmacokinetics showed linear characteristics. Results: Dose-normalized pitavastatin AUCs for *1b/*1b (group 1), *1a/*1a or *1a/*1b (group 2), and *1a/*15 or *1b/*15 (group 3) were 38.8 +/- 13.3, 54.4 +/- 12.4, and 68.1 +/- 16.3 ng center dot h center dot mL(-1) center dot mg(-1) (mean +/- SD), respectively, with significant differences between all 3 groups (P =.008) and between subjects carrying and those not carrying the * 15 allele (P =.004). Doge-normalized pitavastatin C-max values were 13.2 +/- 3.3, 18.2 +/- 5.7, and 29.4 +/- 9.6 ng center dot mL(-1) center dot mg(-1) in groups 1, 2, and 3, respectively, and also showed significant differences (P =.003) in a manner similar to that shown by AUC. No significant differences were found between the genotype groups in terms of dose-normalized AUC or C-max. values of pitavastatin lactone. Conclusion: OATP1B1 variant haplotypes were found to have a significant effect on the pharmacokinetics; of pitavastatin. These results suggest that the *15 allele is associated with decreased pitavastatin uptake from blood into hepatocytes and that OATP1B1 genetic polymorphisms have no effect on the pharmacokinetics of pitavastatin lactone.