Clinical and Pharmacogenetic Predictors of Circulating Atorvastatin and Rosuvastatin Concentration in Routine Clinical Care

• Original Article

Clinical and Pharmacogenetic Predictors of Circulating Atorvastatin and Rosuvastatin Concentration in Routine Clinical Care

1. Marianne K. DeGorter1,


2. Rommel G. Tirona1,


3. Ute I. Schwarz1,


4. Yun-Hee Choi2,


5. George K. Dresser3,


6. Neville Suskin4,


7. Kathryn Myers3,


8. GuangYong Zou2,


9. Otito Iwuchukwu5,


10. Wei-Qi Wei5,


11. Russell A. Wilke5,


12. Robert A. Hegele6 and


13. Richard B. Kim1*

+ Author Affiliations

1. 
   ¹Departments of Medicine & Physiology and Pharmacology, The University of Western Ontario, London, Canada
   
   


2. 
   ²Department of Epidemiology & Biostatistics, The University of Western Ontario, London, Canada
   
   


3. 
   ³Department of Medicine, The University of Western Ontario, London, Canada
   
   


4. 
   ⁴Departments of Medicine & Epidemiology and Biostatistics, The University of Western Ontario, London, Canada
   
   


5. 
   ⁵Robarts Research Institute, The University of Western Ontario, London, Canada
   
   


6. 
   ⁶Department of Medicine & Robarts Research Institute, The University of Western Ontario, London, Canada
   
   

1. ↵* ALL–152 LHSC — University Hospital, 339 Windermere Road, London, Ontario N6A 5A5 Canada richard.kim@lhsc.on.ca

Abstract

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 gender, 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 R² = 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 R² = 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 90^th 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 if this approach reduces incidence of statin-myopathy.

Key Words:

• drug transporters


• statin therapy


• pharmacogenetics


• pharmacokinetics

• Received December 13, 2012.


• Revision received June 25, 2013.


• Accepted July 17, 2013.