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Clinical and Pharmacogenetic Predictors of Circulating Atorvastatin and Rosuvastatin Concentrations in Routine Clinical Care
Open accessAbstract
Background—: A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients. Methods and Results—: In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for sex, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T>C ( P <0.001) and ABCG2 c.421C>A ( P <0.01) were important to rosuvastatin concentration (adjusted R 2 =0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A>G ( P <0.01) and c.521T>C ( P <0.05) and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R 2 =0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient’s risk–benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile. Conclusions—: Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine whether this approach reduces incidence of statin myopathy.
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“While genetic testing in patients with statin myopathy has not yet become commonplace, there are some clear genetic signals, with variants of genes encoding drug transporters in both the liver and skeletal muscle that increase serum statin concentration linked to muscle side effects (see Supplementary material online, Table S5).106–109”
From Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management (2015) · cites this paper as [109]
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Metadata
- Authors
- DeGorter, M. K., Tirona, R. G., Schwarz, U. I., Choi, Y.-H., Dresser, G. K., Suskin, N., Myers, K., Zou, G., Iwuchukwu, O., Wei, W.-Q., Wilke, R. A., Hegele, R. A., & Kim, R. B.
- Affiliations
- Western University (CA)
- ORCID
- Venue
- Circulation: Cardiovascular Genetics
- Published
- 2013-08
- Volume
- 6
- Issue
- 4
- Pages
- 400-408
- ISSN
- 1942-325X (ISSN-L)
- 1942-3268
- PMC
- PMC3922121
- OpenAlex
- W2164884234
- Cited by
- 195
- References
- 50
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 8 · 2023: 17 · 2022: 15 · 2021: 17 · 2020: 23 · 2019: 16 · 2018: 20 · 2017: 11 · 2016: 21 · 2015: 11 · 2014: 16 · 2013: 4
- FWCI
- 18.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Cardiovascular Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Scholarship@Western (Western University) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-89753)
- National Institute of General Medical Sciences (T32GM007569)
- National Center for Research Resources (UL1RR024975)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- atorvastatin, rosuvastatin, statin-induced myopathy, pharmacogenetics, SLCO1B1, ABCG2, drug transporter polymorphisms, interindividual variability, 4β-hydroxycholesterol, CYP3A activity, statin dosing, statin safety
- MeSH terms
- Rosuvastatin Calcium, Atorvastatin, ATP Binding Cassette Transporter, Subfamily G, Member 2, Adult, Aged, Aged, 80 and over, Alleles, Cholesterol, Female, Fluorobenzenes, Genotype, Heptanoic Acids, Humans, Hydroxycholesterols, Hypercholesterolemia, Male, Middle Aged, Neoplasm Proteins, Polymorphism, Genetic, Prospective Studies, Pyrimidines, Pyrroles, Retrospective Studies, Sulfonamides, Cohort Studies, Linear Models, Databases, Factual, ATP-Binding Cassette Transporters, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Polymorphism, Single Nucleotide, Organic Anion Transporters, Liver-Specific Organic Anion Transporter 1, Cytochrome P-450 CYP3A
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