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Supplements Preventive Medicine in Managed Care - Statin Drug Interactions and Implications for Managed Care
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Statins and Potentially Interacting Medications: A Managed Care Perspective
Lida Etemad, PharmD, MS
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Safety and Statins: Pharmacologic and Clinical Perspectives
Michael B. Bottorff, PharmD

Safety and Statins: Pharmacologic and Clinical Perspectives

Michael B. Bottorff, PharmD

Atorvastatin, simvastatin, and lovastatin are metabolized by CYP3A4 and are subject to interactions with a long list of substances, including macrolide antibiotics (but not azithromycin), azole antifungals, amiodarone, verapamil and diltiazem (but not the dihydropyridine calcium channel blockers), cyclosporine, protease inhibitors, and grapefruit juice. For example, when simvastatin is used alone, the incidence of myopathy is less than 0.1%; but when used in combination with amiodarone, the incidence rises sharply to 6%. 8

Fluvastatin is metabolized by CYP2C9 and is subject to potential interactions with agents such as amiodarone, gemfibrozil, fluconazole, metronidazole, and fluoxetine.However, in contrast to the relatively weak binding of simvastatin, atorvastatin, and lovastatin for CYP3A4, fluvastatin binds strongly to CYP2C9 and may inhibit the metabolism of the other agents that depend on this isoenzyme, such as warfarin.

Because rosuvastatin is relatively water-soluble, increased drug levels may result from severely diminished renal function. Approximately 10% of its elimination results from metabolism by CYP2C9 and CYP2C19. Interactions can occur with gemfibrozil (an inhibitor of both isoenzymes, resulting in an approximate doubling of rosuvastatin exposure), 9 and theoretically with fluconazole, fluoxetine, fluvoxamine, and omeprazole as well. In addition, rosuvastatin drug levels are roughly twice as high in Japanese and Chinese people living in Asia than in Caucasian people living in Europe or North America. 9 These differences may be caused by environmental factors or may, in part, reflect the fact that a genetic inability to produce CYP2C19 is found in 10% to 20% of the Japanese population compared with 3% to 5% of the Caucasian population 10 ; further study of these differences is needed.

Figure 4. Increase in atorvastatin exposure when used in conjunction with itraconazole versus placebo.
				
				Source: Kantola T, et al.
				Clin Pharmacol Ther
				. 1998; 64:58-65.
Figure 4. Increase in atorvastatin exposure when used in conjunction with itraconazole versus placebo.
Source: Kantola T, et al. Clin Pharmacol Ther . 1998; 64:58-65.

Pravastatin is water soluble and does not depend on CYP450-mediated metabolism; it does, however, undergo acid hydrolysis and hepatic conjugation, and elimination occurs through renal and biliary excretion. In patients with diminished renal function, nonrenal mechanisms tend to increase in compensation, preventing accumulation and increased drug concentrations.

To quantify the effects of pharmacokinetic interactions between CYP3A4-dependent statins and CYP3A4 inhibitors, simvastatin exposure, measured as area under the concentration- time curve, was increased 4- to 10-fold when the statin was used in conjunction with known CYP3A4 inhibitors versus placebo (Figure 2). 11,12 Similarly, lovastatin exposure was increased 3.6- to 20-fold when used in conjunction with CYP3A4 inhibitors versus placebo (Figure 3). 13-16 Exposure to atorvastatin in active acid and lactone forms was increased 3- and 4-fold when used in conjunction with itraconazole versus placebo (Figure 4). 17 Because atorvastatin is less dependent than simvastatin or lovastatin on metabolism via CYP3A4, it may be less sensitive to pharmacokinetic interactions with CYP3A4 inhibitors.

Other Types of Statin Interactions

As previously stated, the active acid forms of the statins undergo hepatic glucuronidation, and the fibrates block glucuronide. It is now known that gemfibrozil is a more potent glucuronide blocker than fenofibrate. 18 When gemfibrozil is given concurrently with simvastatin or lovastatin, the statin levels increase roughly 3-fold. Fenofibrate, in contrast, has no effect on statin concentrations.

The interactions between statins and warfarin are complex. Warfarin goes through several different CYP450 pathways, any of which might serve as a source of interactions with statins. However, whereas most of the interactions previously described result in inhibited statin metabolism, interactions with warfarin tend to work in the opposite direction and inhibit warfarin metabolism.The clinical result is an increase in the international normalized ratio (INR), a standardized measure of prothrombin time. The CYP3A4-dependent statins (simvastatin, lovastatin, and atorvastatin) all have the potential to raise the INR in patients taking warfarin; the effect is variable, and monitoring INR is important to determine whether the warfarin dosage must be adjusted.

Fluvastatin, metabolized through the CYP2C9 pathway, can also interfere with warfarin metabolism and raise the INR.19 Rosuvastatin can raise the INR without raising warfarin concentrations, which implies that its effect is not mediated through the CYP450 system but is more likely caused by a partial displacement of warfarin from its protein-bound state in circulation. 20 Pravastatin is unique among the statins in that it produces no change in the INR in patients taking warfarin, which demonstrates its lack of involvement in the CYP450 pathways and an absence of effects on warfarin protein binding.

Selecting Statin Therapy

Patients most often start receiving statin therapy for the purpose of lowering concentrations of LDL cholesterol; other goals in improving the lipid profile include elevating high-density lipoprotein (HDL) cholesterol and lowering triglycerides. Subsequent clinical decisions are made if any of these goals are not met by the initially chosen regimen. 21 For example, if LDL cholesterol remains elevated, options include increasing the dose of the statin or adding niacin to the statin, although these strategies would incur an increased risk of toxicity. Other agents that may be added to the statin regimen are fenofibrate (although it is relatively weak in terms of reducing LDL cholesterol), ezetimibe (a cholesterol absorption inhibitor), and bile acid sequestrants. If the HDL cholesterol remains low or triglycerides remain high, fibrates or niacin may be added, but again at the cost of an increased risk of toxicity. Another option for reducing triglyceride levels is the addition of fish oils (omega-3 fatty acids) to the regimen.

Figure 5. The likelihood of drugódrug interactions rises sharply with the number of medications in use. Other factors affecting the likelihood of clinically relevant interactions include age and the severity and chronicity of disease.
				
				Sources: Williams, et al. Ir
				J Med Sci
				. 1999; Weideman, et al.
				Hosp Pharm
				. 1998; 33:835-840.
Figure 5. The likelihood of drugódrug interactions rises sharply with the number of medications in use. Other factors affecting the likelihood of clinically relevant interactions include age and the severity and chronicity of disease.
Sources: Williams, et al. Ir J Med Sci . 1999; Weideman, et al. Hosp Pharm . 1998; 33:835-840.

An additional safety concern when drugs are added to a statin regimen is that the likelihood of interactions rises sharply with polypharmacy. When more than 2 drugs are taken, the theoretical number of possible interactions is computed as N! divided by 2(Nó2)! (the exclamation point indicates the factorial of the number: for example, 4!=4x3x2). Realistically, the likelihood of an interaction when 8 drugs are taken is roughly 90% (Figure 5) (Williams, et al. Ir J Med Sci. 1999; Weideman, et al. Hosp Pharm. 1998;33:835- 840). Interactions are not always serious or clinically apparent, but it is obvious that as more drugs compete for common CYP450 pathways, the risk of a clinically-relevant interaction increases. For patients taking multiple medications, it is especially important to select agents that are least likely to incur an additional risk of interaction; for patients who require the addition of lipid-lowering pharmacotherapy to a drug regimen that is already complex, the preferred agents would be the statins that are least dependent on the CYP450 system in general and on CYP3A4 in particular.

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  3. Phillips PS, Haas RH, Bannykh S, et al. . Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med . 2002;137:581-585.

  4. Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. . ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol . 2002;40:567-572.

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  6. Michalets EL . Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy . 1998;18:84-112.

  7. Jacobson TA . Combination lipid-lowering therapy with statins: safety issues in the postcerivastatin era. Expert Opin Drug Saf . 2003;2:269-286.

  8. Zocor (simvastatin) prescribing information. Merck & Co, Inc; 2004.

  9. Crestor (rosuvastatin) prescribing information. AstraZeneca Pharmaceuticals LP; 2004.

  10. Weber WW . Populations and polymorphisms. Presentation at Pharmacogenetics in Patient Care, American Association for Clinical Chemistry. Chicago, November 6, 1998.Available at: www.aacc.org/pharmacogenetics . Accessed September 7, 2004.

  11. Kantola T, Kivisto KT, Neuvonen PJ . Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther . 1998;64:177-182.

  12. Neuvonen PJ, Kantola T, Kivisto KT . Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther . 1998;63:332-341.

  13. Olbricht C,Wanner C, Eisenhauer T, et al. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Ther . 1997;62:311-321.

  14. Neuvonen PJ, Jalava KM . Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther . 1996;60:54-61.

  15. Azie NE, Brater DC, Becker PA, et al. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther . 1998;64:369-377.

  16. Bottorff MB, et al. Differences in in vitro metabolism of pravastatin and lovastatin as assessed by CXP3A4 inhibition with erythromycin. Pharmacotherapy . 1997;184-185. [abstract].

  17. Kantola T, Kivisto KT, Neuvonen PJ . Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther. 1998;64:58-65.

  18. Prueksaritanont T, Zhao JJ, Ma B, et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther. 2002;301:1042-1051.

  19. Andrus MR . Oral anticoagulant drug interactions with statins: case report of fluvastatin and review of the literature. Pharmacotherapy. 2004;24:285-290.

  20. Barry M. Rosuvastatin-warfarin drug interaction. Lancet . 2004;363:328.

  21. Grundy SM. Alternative approaches to cholesterol-lowering therapy. Am J Cardiol . 2002;90:1135-1138.

  22. Freedman JE, Becker RC,Adams JE, et al. Medication errors in acute cardiac care: An American Heart Association scientific statement from the Council on Clinical Cardiology Subcommittee on Acute Cardiac Care, Council on Cardiopulmonary and Critical Care, Council on Cardiovascular Nursing, and Council on Stroke. Circulation . 2002;106:2623-2629.

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