Identification of Genetic Variants Associated with Pravastatin and Pitavastatin Pharmacokinetics.

Abstract

A clinical trial was carried out to investigate the pharmacogenetics of single-dose pravastatin and pitavastatin pharmacokinetics in 173 and 164 healthy participants. Additionally, 96 participants were included from previous pharmacogenetic studies with pravastatin. In a genome-wide meta-analysis of pravastatin including all 269 participants, SLCO1B1 c.521T>C (rs4149056) was associated with increased AUC_0-∞ (P = 9.8 × 10^-12). Similarly, SLCO1B1 c.521T>C was genome-wide significantly associated with increased AUC_0-∞ of pitavastatin (P = 9.7 × 10^-15). Candidate gene analyses suggested that participants with increased function SLCO1B1 variants had decreased pravastatin exposure. Furthermore, decreased function CYP2C9 variants may increase pitavastatin and pitavastatin lactone exposure. Compared to participants with normal function SLCO1B1 genotype, the AUC_0-∞ of pravastatin was 140% (90% confidence interval: 86-210%; P = 4.7 × 10^-8) and 37% (20-56%; P = 1.1 × 10^-4) greater in participants with poor and decreased function SLCO1B1 genotype, respectively, while participants with highly increased function SLCO1B1 genotype had a 60% (39-75%; P = 6.0 × 10^-4) lower AUC_0-∞. The AUC_0-∞ of pitavastatin was 153% (100-222%; P = 1.6 × 10^-9) and 35% (8-69%; P = 0.027) greater in participants with poor and decreased function SLCO1B1 genotype, respectively, than in those with normal function SLCO1B1 genotype. Participants with intermediate metabolizer CYP2C9 genotype had 18% (3-34%; P = 0.046) greater AUC_0-∞ of pitavastatin than those with normal metabolizer CYP2C9 genotype. This study demonstrates the important role of SLCO1B1 in pravastatin and pitavastatin pharmacokinetics and suggests that CYP2C9 variants also affect the pharmacokinetics of pitavastatin.