Abstract 14993: Drug Transporter Polymorphisms and Age Predict Circulating Atorvastatin and Rosuvastatin Concentration in Patients
Background: Statins are effective in reducing risk for major cardiovascular events, and are prescribed to nearly 10% of adults in developed countries. A significant barrier to statin therapy is muscle toxicity, which is associated with elevated systemic drug exposure. Despite numerous clinical trials to assess statin safety and effectiveness, there is little understanding of the normal range of plasma concentrations in patients, or the impact of clinical and pharmacogenetic variables on observed statin levels in patients.
Methods: We prospectively recruited 299 patients and measured statin concentrations by liquid chromatography-mass spectrometry (LCMS). We assessed the contribution of clinical variables and polymorphisms in transporter genes SLCO1B1, SLCO1B3, SLCO2B1, ABCG2, ABCC2, and ABCB1 to statin concentration using multiple linear regression models.
Results: We observed up to 45-fold variation in atorvastatin and rosuvastatin concentrations among patients taking the same dose. After adjustment for gender, 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 significantly associated with rosuvastatin concentration, whereas SLCO1B1 c.388A>G (p<0.01) and c.521T>C (p<0.05) were significant for atorvastatin. 4β-hydroxycholesterol, a marker of CYP3A activity, was associated with atorvastatin, but not rosuvastatin concentration. Advanced age was associated with higher concentrations of both atorvastatin and rosuvastatin. For rosuvastatin, 88% of the explainable variability was attributable to transporter genetics; for atorvastatin, transporter genetics and metabolism together contributed to almost 70%.
Conclusion: Drug transporter polymorphisms accounted for most of the explainable variability in statin levels. Based on our data, a genomics-guided dosing algorithm to avoid high statin levels is described. Controlled randomized trials are needed to determine if this approach reduces rate of statin-myopathy.
- © 2012 by American Heart Association, Inc.