Genomewide Association Study of Simvastatin Pharmacokinetics

Anssi J H Mykkänen; Suvi Taskinen; Mikko Neuvonen; Maria Paile-Hyvärinen; E Katriina Tarkiainen; Tuomas Lilius; Tuija Tapaninen; Janne T Backman; Aleksi Tornio; Mikko Niemi

doi:10.1002/cpt.2674

Genomewide Association Study of Simvastatin Pharmacokinetics

Clin Pharmacol Ther. 2022 Sep;112(3):676-686. doi: 10.1002/cpt.2674. Epub 2022 Jun 24.

Authors

Anssi J H Mykkänen^{1

2}, Suvi Taskinen^{1

2}, Mikko Neuvonen^{1

2}, Maria Paile-Hyvärinen^{1

2}, E Katriina Tarkiainen^{1

2}, Tuomas Lilius^{1

2}, Tuija Tapaninen^{1

2}, Janne T Backman^{1

2}, Aleksi Tornio^{1

2}, Mikko Niemi^{1

2}

Affiliations

¹ Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
² Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.

Abstract

We investigated genetic determinants of single-dose simvastatin pharmacokinetics in a prospective study of 170 subjects and a retrospective cohort of 59 healthy volunteers. In a microarray-based genomewide association study with the prospective data, the SLCO1B1 c.521T>C (p.Val174Ala, rs4149056) single nucleotide variation showed the strongest, genomewide significant association with the area under the plasma simvastatin acid concentration-time curve (AUC; P = 6.0 × 10^-10 ). Meta-analysis with the retrospective cohort strengthened the association (P = 1.6 × 10^-17 ). In a stepwise linear regression candidate gene analysis among all 229 participants, SLCO1B1 c.521T>C (P = 1.9 × 10^-13 ) and CYP3A4 c.664T>C (p.Ser222Pro, rs55785340, CYP3A4*2, P = 0.023) were associated with increased simvastatin acid AUC. Moreover, the SLCO1B1 c.463C>A (p.Pro155Thr, rs11045819, P = 7.2 × 10^-6 ) and c.1929A>C (p.Leu643Phe, rs34671512, P = 5.3 × 10^-4 ) variants associated with decreased simvastatin acid AUC. Based on these results and the literature, we classified the volunteers into genotype-predicted OATP1B1 and CYP3A4 phenotype groups. Compared with the normal OATP1B1 function group, simvastatin acid AUC was 273% larger in the poor (90% confidence interval (CI), 137%, 488%; P = 3.1 × 10^-6 ), 40% larger in the decreased (90% CI, 8%, 83%; P = 0.036), and 67% smaller in the highly increased function group (90% CI, 46%, 80%; P = 2.4 × 10^-4 ). Intermediate CYP3A4 metabolizers (i.e., heterozygous carriers of either CYP3A4*2 or CYP3A4*22 (rs35599367)), had 87% (90% CI, 39%, 152%, P = 6.4 × 10^-4 ) larger simvastatin acid AUC than normal metabolizers. These data suggest that in addition to no function SLCO1B1 variants, increased function SLCO1B1 variants and reduced function CYP3A4 variants may affect the pharmacokinetics, efficacy, and safety of simvastatin. Care is warranted if simvastatin is prescribed to patients carrying decreased function SLCO1B1 or CYP3A4 alleles.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Cytochrome P-450 CYP3A / genetics
Genotype
Humans
Liver-Specific Organic Anion Transporter 1 / genetics
Organic Anion Transporters* / genetics
Polymorphism, Single Nucleotide
Prospective Studies
Retrospective Studies
Simvastatin* / pharmacokinetics

Substances

Liver-Specific Organic Anion Transporter 1
Organic Anion Transporters
SLCO1B1 protein, human
Simvastatin
Cytochrome P-450 CYP3A
CYP3A4 protein, human