(T1330-10-68) Effects of Clarithromycin on the Pharmacokinetics of Pitavastatin and Its Lactone Metabolite in Different SLCO1B1 Diplotypes

Purpose: Pitavastatin, a 3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is used to treat dyslipidemia. OATP1B1, encoded by the SLCO1B1 gene, primarily contributes to the hepatic uptake of pitavastatin in humans. OATP1B1 transporter is genetically polymorphic and it can affect the inter-individual pharmacokinetic variability of pitavastatin. Clarithromycin, one of the macrolide antibiotics, is a potent inhibitor of OATP1B1. In this study, we investigated the effects of clarithromycin on the pharmacokinetics of pitavastatin in different SLCO1B1 diplotypes.

Methods: Twenty-nine healthy Korean subjects were enrolled and divided into three different SLCO1B1 diplotypes: SLCO1B1*1a/*1b (n=13), *1b/*15 (n=13) and *15/*15 (n=3). In the control phase, all participants were administered a 2 mg single oral dose of pitavastatin. After a washout period, 500 mg of clarithromycin were received 12 hours before and at 0, 12, 24 and 36 hours after the administration of a 2 mg single oral dose of pitavastatin (clarithromycin phase). The plasma concentrations of pitavastatin and its lactone metabolite were determined by HPLC-MS/MS.

Results: In the control phase, AUC_inf, C_max and CL/F of pitavastatin were markedly different in different SLCO1B1 diplotypes (all, p< 0.01). After clarithromycin treatment, AUC_inf and CL/F of pitavastatin were significantly different in different SLCO1B1 genotypes (all, p< 0.05), but not C_max of pitavastatin (p=0.099). AUC_inf, C_max and CL/F of pitavastatin were significantly altered in the concomitant use of clarithromycin compared to the control phase in SLCO1B1*1a/*1b and *1b/*15 genotypes, respectively (all, p< 0.05), whereas there were no significant differences in SLCO1B1*15/*15 genotype (all, p >0.05). For its metabolite, no considerable alterations in relation to SLCO1B1 variants were not found and only C_max in SLCO1B1*1a/*1b genotype was significantly decreased by clarithromycin coadministration (p=0.0489).

Conclusion: Genetic polymorphism of SLCO1B1 and clarithromycin coadministration significantly affected the pharmacokinetics of pitavastatin but to a lesser extent its lactone metabolite.

Figure 1. Plasma concentration-time profiles for pitavastatin and pitavastatin lactone during control and clarithromycin phases in SLCO1B1*1a/*1b, SLCO1B1*1b/*15, and SLCO1B1*15/*15 genotype groups. The data during control and clarithromycin phases are given as closed rectangles and open circles, respectively.

Table 1. Pharmacokinetic parameters of pitavastatin and pitavastatin lactone during control and clarithromycin phases in SLCO1B1*1a/*1b, SLCO1B1*1b/*15, and SLCO1B1*15/*15 genotype groups.