Mykkänen Anssi J H, Tarkiainen E Katriina, Taskinen Suvi, Neuvonen Mikko, Paile-Hyvärinen Maria, Lilius Tuomas O, Tapaninen Tuija, Backman Janne T, Tornio Aleksi, Niemi Mikko
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.
Clin Pharmacol Ther. 2025 Jun;117(6):1763-1774. doi: 10.1002/cpt.3623. Epub 2025 Mar 3.
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 (P = 9.8 × 10). Similarly, SLCO1B1 c.521T>C was genome-wide significantly associated with increased AUC of pitavastatin (P = 9.7 × 10). 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 of pravastatin was 140% (90% confidence interval: 86-210%; P = 4.7 × 10) and 37% (20-56%; P = 1.1 × 10) 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) lower AUC. The AUC of pitavastatin was 153% (100-222%; P = 1.6 × 10) 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 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.
开展了一项临床试验，以研究173名和164名健康参与者中辛伐他汀单剂量及匹伐他汀药代动力学的药物遗传学。此外，96名参与者来自之前关于辛伐他汀的药物遗传学研究。在一项纳入所有269名参与者的辛伐他汀全基因组荟萃分析中，SLCO1B1基因c.521T>C（rs4149056）与AUC增加相关（P = 9.8×10）。同样，SLCO1B1基因c.521T>C在全基因组范围内与匹伐他汀的AUC增加显著相关（P = 9.7×10）。候选基因分析表明，具有功能增强的SLCO1B1变异体的参与者辛伐他汀暴露量降低。此外，功能降低的CYP2C9变异体可能会增加匹伐他汀和匹伐他汀内酯的暴露量。与具有正常功能的SLCO1B1基因型参与者相比，功能较差和降低的SLCO1B1基因型参与者的辛伐他汀AUC分别高140%（90%置信区间：86 - 210%；P = 4.7×10）和37%（20 - 56%；P = 1.1×10），而功能显著增强的SLCO1B1基因型参与者的AUC低60%（39 - 75%；P = 6.0×10）。功能较差和降低的SLCO1B1基因型参与者的匹伐他汀AUC分别比具有正常功能的SLCO1B1基因型参与者高153%（100 - 222%；P = 1.6×10）和35%（8 - 69%；P = 0.027）。具有中间代谢型CYP2C9基因型的参与者的匹伐他汀AUC比具有正常代谢型CYP2C9基因型的参与者高18%（3 -
