SLCO1B1 Phenotype and CYP3A5 Polymorphism Significantly Affect Atorvastatin Bioavailability

Area of Science:

• Pharmacogenetics
• Clinical Pharmacology
• Drug Metabolism and Transport

Background:

• Atorvastatin effectively reduces cardiovascular events but is associated with myopathy, leading to treatment discontinuation.
• Genetic factors influence atorvastatin pharmacokinetics, yet guidelines for its use are less developed compared to other statins.
• The Dutch Pharmacogenetics Working Group (DPWG) suggests genotype-based dosing adjustments for atorvastatin to mitigate myopathy risk.

Purpose of the Study:

• To investigate the impact of genetic variants, including SLCO1B1, CYP3A4/5, UGT enzymes, and SLC transporters, on atorvastatin pharmacokinetics.
• To identify key genetic predictors of atorvastatin exposure variability in healthy volunteers.

Main Methods:

• A candidate-gene pharmacogenetic study involving 156 healthy volunteers undergoing atorvastatin bioequivalence trials.
• Genotyping of 60 variants across 15 genes.
• Analysis of pharmacokinetic parameters (AUC, Cmax, Vd/F, tmax) adjusted for dose/weight (DW).

Main Results:

• SLCO1B1 phenotype was the strongest predictor of atorvastatin AUC/DW and Cmax/DW (p < 0.001).
• CYP3A5*3 genotype significantly affected atorvastatin AUC/DW (p = 0.004) and Cmax/DW (p = 0.018).
• Secondary findings implicated SLC22A1 and UGT2B7 variants in atorvastatin Cmax/DW, Vd/F, and tmax.

Conclusions:

• SLCO1B1 genotype is a crucial determinant of atorvastatin pharmacokinetic variability, supporting its use for personalized dosing.
• The Clinical Pharmacogenetics Implementation Consortium (CPIC) should consider including atorvastatin in its statin-SLCO1B1 guidelines.
• Novel associations with CYP3A5 warrant further investigation to optimize atorvastatin therapy.