Drug-drug interactions and statin therapy.

Drug-drug interactions (DDIs) among widely and chronically prescribed medications are a relevant health issue in clinical practice. Reported incidences in outpatients range from 9.2% to 70.3% for drug interactions of any severity and from 1.2% to 23.3% for those considered of major relevance. (1-3) Due to the progressive population ageing in Western Countries, concern has been raised about risks of clinically relevant DDI, as a result of polytherapy. Indeed, elderly patients may have multiple disease states and, therefore, may require a variety of different drugs. According to a recent study, (4) the elderly population uses on average 7.0 drugs per person. In addition to polypharmacy, other factors such as age-related physiologic changes, concomitant diseases, genetic constitution and diet may alter drug response, thus predisposing patients to adverse effects and drug interactions. (5)

Drug-drug interactions may lead to adverse drug reactions that can be severe enough to require hospitalization, (6) with the proportion of hospital admissions due to DDIs ranging from 0% to 3.8%. (7-8) However, combinations of potentially interacting drugs do not necessarily result in adverse clinical manifestations, if they are knowingly prescribed and properly managed. Pharmacokinetic drug interactions in particular are often manageable, and their risk may be lessened by dose adjustment. (9) Otherwise, the burden of drug-drug interaction, in terms of patient's safety, may be reduced by preventing concomitant use of potentially interacting drugs and, whenever possible, by replacing drugs at interaction risk with effective but safer alternative medications belonging to the same drug class. It is the case of statins that undergoes different metabolism via cytochrome P-450 (CYP) superfamily: lovastatin, simvastatin and atorvastatin are mostly metabolized by CYP3A isoenzymes, fluvastatin by CYP2C9, while pravastatin and rosuvastatin are not significantly metabolized by this system. (10)

Although statins are the most widely used lipid lowering agents, physicians seem to be not adequately aware about their pharmacokinetic properties, and, consequently, about their interaction risk. Indeed, coprescribing of statins with potentially interacting medications, despite availability of therapeutic alternatives, has been previously reported in general practice. (11-12)

In this issue of the Southern Medical Journal, (13) authors describe a case report of drug-drug interaction in a 61-year-old patient who was chronically treated with atorvastatin (plus ezetimibe and niacin) and antiseizure drugs, phenobarbital and phenytoin. Interestingly, lipid lowering therapy was successful only after phenytoin discontinuation. This paper supports the key role of CYP3A4 isoenzyme in pharmacokinetic interactions of statins. In this circumstance, phenytoin, as CYP3A4 inducer, may have reduced atorvastatin effectiveness by increasing its metabolism. In addition, this case report highlights that concomitant prescription of statins and other drugs at interaction risk may lead not only to potentially severe DDIs, but to lipid lowering ineffectiveness as well.

In conclusion, inhibitors, as well as inducers of CYP3A4 isoenzyme, might be the cause of potential drug interactions with statins, as suggested by this case report. Clinicians should be aware of the most frequently observed drug-statin interactions and how these interactions can be avoided. On the other hand, health national systems should implement prevention strategies targeted to increase the awareness of health professionals about the interaction risks of widely prescribed drugs, like statins, and, finally, to improve the management of polytherapy.

References

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2. Rosholm JU, Bjerrum L, Hallas J, et al. Polypharmacy and the risk of drug-drug interactions among Danish elderly. A prescription database study. Dan Med Bull 1998;45:210-213.

3. Bjerrum L, Andersen M, Petersen G, et al. Exposure to potential drug interactions in primary health care. Scand J Prim Health Care 2003;21:153-158.

4. Bjorkman IK, Fastbom J, Schmidt IK, Bernsten CB, Pharmaceutical Care of the Elderly in Europe Research (PEER) Group. Drug-drug interactions in the elderly. Ann Pharmacother 2002;36:1675-1681.

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7. Raschetti R, Morgutti M, Menniti-Ippolito F, et al. Suspected adverse drug events requiring emergency department visits or hospital admissions. Eur J Clin Pharmacol 1999;54:959-963.

8. Jankel CA, Fitterman LK. Epidemiology of drug-drug interactions as a cause of hospital admissions. Drug Saf 1993;9:51-59.

9. Bergk V, Gasse C, Rothenbacher D, et al. Drug interactions in primary care: impact of a new algorithm on risk determination. Clin Pharmacol Ther 2004;76:85-96.

10. Corsini A, Bellosta S, Baetta R, et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 1999;84:413-428.

11. Piacentini N, Trifiro G, Tari M, et al, UVEC group. Statin-macrolide interaction risk: a population-based study throughout a general practice database. Eur J Clin Pharmacol 2005;61:615-620.

12. Ratz Bravo AE, Tchambaz L, Krahenbuhl-Melcher A, et al. Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy. Drug Saf 2005;28:263-275.

13. Khandwala HM. Lipid lowering inefficacy of high-dose statin therapy due to concurrent use of phenytoin South Med J 2006;99:1385-1387.

Gianluca Trifiro, MD

From the Department of Clinical and Experimental Medicine and Pharmacology-Section of Pharmacology Policlinico Universitario, Via Consolare Valeria-Gazzi, and IRCCS Centro Neurolesi "Bonino-Pulejo," Messina, Italy.

Reprint requests to Gianluca Trifiro, MD, University of Messina, Pharmacology Unit, Messina, Italy. Email: [e-mail]

Accepted August 10, 2006.