ORIGINAL REPORT Influence of genetic variation in CYP3A4 and ABCB1 on dose decrease or switching during simvastatin and atorvastatin therapy y Matthijs L. Becker PharmD 1,2 , Loes E. Visser PhD PharmD 1,2 , Ron H. N. van Schaik PhD 3,4 , Albert Hofman PhD MD 1,5 , Andre ´ G. Uitterlinden PhD 1,5,6 and Bruno H. Ch. Stricker MB PhD 1,5,6,7 * 1 Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands 2 Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands 3 Department of Clinical Chemistry, Erasmus MC, Rotterdam, the Netherlands 4 STAR Medical Diagnostic Center, Rotterdam, the Netherlands 5 Member of the Netherlands Consortium on Healthy Aging, Leiden / Rotterdam, the Netherlands 6 Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands 7 Drug Safety Unit, Inspectorate for Health Care, The Hague, the Netherlands SUMMARY Purpose Simvastatin and atorvastatin are metabolized by the CYP3A4 enzyme and transported by the ABCB1 transporter. We studied whether the polymorphism CYP3A4  1B and the polymorphisms C1236T, G2677A/T and C3435T in the ABCB1 gene were associated with a decrease of the prescribed dose or a switch to another cholesterol lowering drug during simvastatin and atorvastatin therapy. These events may indicate that statin plasma levels were too high and resulted in an adverse drug reaction or a too strong reduction in cholesterol level. Methods We identified 1239 incident simvastatin and atorvastatin users in the Rotterdam Study, a population-based cohort study. Associations between the polymorphisms in the CYP3A4 and ABCB1 gene and the time to a decrease in dose or a switch to another cholesterol lowering drug were studied using Cox proportional hazards. Results Simvastatin and atorvastatin users with the CYP3A4  1B variant G allele had a lower risk (HR 0.46; 95%CI 0.24–0.90) for these events than users with the wild-type AA genotype. No significant associations were found for the ABCB1 polymorphisms. The association with the CYP3A4  1B polymorphism was found in women (HR 0.33; 95%CI 0.12–0.89) and was non-significant in men (HR 0.69 95%CI 0.28–1.70). This association was stronger in patients with the ABCB1 3435T variant allele versus the G allele. Conclusion In simvastatin and atorvastatin users, the CYP3A4  1B G allele is associated with a lower risk of elevated statin plasma levels, particularly in women and in users with the ABCB1 3435T variant allele. Copyright # 2009 John Wiley & Sons, Ltd. key words — simvastatin; atorvastatin; pharmacogenetics; ABCB1; CYP3A4 Received 28 January 2009; Revised 30 July 2009; Accepted 27 August 2009 INTRODUCTION HMG-CoA reductase inhibitors or statins are widely prescribed for the treatment of hypercholesterolemia. Statins reduce morbidity and mortality by lowering LDL cholesterol levels. 1 In general statins are well tolerated and safe, although myopathy and rhabdo- myolysis are well-known serious adverse reactions associated with statin therapy. 2 Two regularly used statins, simvastatin and atorvas- tatin, are mainly metabolized by the Cytochrome P450 (CYP) 3A4 enzyme. 3–6 The area under curve (AUC) of simvastatin increases five- to twentyfold if itraconazol, a potent CYP3A4 inhibitor, is co-prescribed, and the AUC of atorvastatin increases two to fourfold. 7 The risk of myopathy with these statins is markedly increased if combined with drugs inhibiting CYP3A4 enzymes. 7,8 Genetic variation in the CYP3A4 gene affects the metabolism of simvastatin and atorvastatin. 9 The polymorphism CYP3A4  1B (392A > G) is located in the promotor region of the CYP3A4 gene, and the G allele is assumed by some to be associated pharmacoepidemiology and drug safety 2010; 19: 75–81 Published online 2 October 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/pds.1866 *Correspondence to: Dr B. H. Ch. Stricker, Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the Netherlands E-mail: b.stricker@erasmusmc.nl y The authors declare that there is no conflict of interest. Copyright # 2009 John Wiley & Sons, Ltd.