Impact of ABCG2 and SLCO1B1 polymorphisms on pharmacokinetics of rosuvastatin, atorvastatin and simvastatin acid in Caucasian and Asian subjects: a class effect? - European Journal of Clinical Pharmacology

Purpose

Systemic exposure to rosuvastatin is approximately double that of Caucasians in Asian subjects. We investigated whether this pattern of increased exposure exists for other statins.

Methods

Plasma exposure following single-dose rosuvastatin 20 mg, atorvastatin 40 mg or simvastatin 40 mg was studied in Chinese, Japanese and Caucasian subjects. Plasma concentrations were determined using LC-MS methods. Impact of polymorphisms in SLCO1B1 (T521>C and A388>G) and in ABCG2 (C421>A) on exposure to rosuvastatin, atorvastatin, simvastatin and simvastatin acid was assessed.

Results

Relative to Caucasians, geometric mean area under the curve from time zero to time of last quantifiable concentration was 86 % (90 % confidence interval (CI), 51–130 %) and 55 % (26–91 %) higher for rosuvastatin in Chinese and Japanese subjects, respectively, 53 % (25–88 %) and 69 % (37–108 %) higher for atorvastatin, 23 % (0–52 %) and 12 % (−0.9–39 %) higher for simvastatin and 28 % (5–56 %) and 34 % (10–64 %) higher for simvastatin acid. Geometric mean maximum drug concentration was also proportionally higher for each statin. Polymorphisms in SLCO1B1 T521>C or ABCG2 C421>A were associated with higher exposure to rosuvastatin, atorvastatin and simvastatin acid (but not simvastatin) within a population, but only the ABCG2 C421>A polymorphism contributed towards between-population exposure differences. In individuals carrying wild-type alleles for both SLCO1B1 and ABCG2, area under the plasma concentration-time curve (AUC) still appeared to be higher for rosuvastatin, atorvastatin and simvastatin acid in Chinese and Japanese subjects compared with Caucasians, respectively.

Conclusion

Increased exposure to statins in Asian subjects versus Caucasians may represent a more general class phenomenon than previously recognized.

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We acknowledge Debra Ennis for her contributions as study delivery director. We thank Kerry Knight and Valerie Moss from Prime Medica Ltd and Maren White from White Quill Ltd who provided medical writing and editorial support funded by AstraZeneca.

Responsibility for opinions, conclusions and interpretation of data lies with the authors.

Sources of financial support

This study was funded by AstraZeneca.

Conflict of interest

B.K. Birmingham, C.T. Azumaya, C. Wei, H.J Ambrose, R. Elsby and S. R. Bujac are all employees of AstraZeneca. R. Mosqueda-Garcia and Y. Chen are former employees of AstraZeneca.

C.T. Azumaya, C. Wei, R. Mosqueda-Garcia, Helen J. Ambrose, R. Elsby and S. R. Bujac hold stock in AstraZeneca.

Author notes

1. Yusong Chen

   Present address: PAREXEL International, Waltham, MA, USA

Authors and Affiliations

1. AstraZeneca, Wilmington, DE, USA

   Bruce K. Birmingham, Connie T. Azumaya, Cheryl Wei, Yusong Chen & Rogelio Mosqueda-Garcia

2. AstraZeneca, Macclesfield, Cheshire, UK

   Sarah R. Bujac, Robert Elsby & Helen J. Ambrose

3. West Chester, PA, USA

   Bruce K. Birmingham

Corresponding author

Correspondence to Bruce K. Birmingham.

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