Pharmacokinetic Interactions Between Statins and Fibrates

Pharmacokinetic Interactions Between Statins and Fibrates Alberto Corsini, PhD,a,* Stefano Bellosta, PhD,a and Michael H. Davidson, MDb,c Concomitant use of a fibrate and a statin may offer a therapeutic advantage to patients with dyslipidemia, especially in patients whose low-density lipoprotein cholesterol is controlled by statins but whose high-density lipoprotein cholesterol or triglycerides, or both, are not within goal. However, concern about drug– drug interactions may preclude optimal use of combination statin-fibrate therapy. This article reviews the pharmacokinetics between statins and fibrates, addressing risks associated with drug– drug interactions and combination therapy. © 2005 Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96[suppl]:44K– 49K)

Numerous clinical trials have substantiated the efficacy of lipid modification in the prevention of coronary artery disease (CAD) in individuals, including patients with the metabolic syndrome. Although monotherapy has been shown to affect lipid parameters favorably, combination therapy is often necessary for comprehensive management of the atherogenic dyslipidemia seen in patients with the metabolic syndrome. However, there often is reluctance to prescribe statins and fibrates concomitantly because of the concern that drug– drug interactions will increase the risk of myopathy and rhabdomyolysis. Although statin therapy rarely has severe adverse effects, interactions with other drugs are possible. Simvastatin, lovastatin, and atorvastatin are biotransformed in the liver primarily by cytochrome P450 (CYP) 3A4 (CYP3A4), and are susceptible to drug interactions when coadministered with potential inhibitors of this enzyme.1,2 As a class of agents, statins manifest different pharmacokinetic properties (Table 1),1,1a,2 specific metabolic pathways (Figure 1),3 and specific mechanisms of metabolism (Table 2)2 that can have an influence on drug– drug interactions. As a result, a number of pharmacologic agents can result in relevant drug interactions with statins (Table 3).4 When examining the risk associated with combination therapy, an overview of issues related to the clearance of statins and drug– drug interactions is helpful in examining specific factors associated with increased risk.

Statin-Fibrate Drug Interaction Risk Reports of statin-associated myopathies, based in part on information from the US Food and Drug Administration

a

Department of Pharmacological Sciences, University of Milan, Milan, Italy; bRadiant Research, Chicago, Illinois, USA; and cPreventive Cardiology Center, Rush University Medical Center, Chicago, Illinois, USA. *Address for reprints: Alberto Corsini, PhD, Department of Pharmacological Sciences, University of Milan, via Balzaretti 9, 20133 Milan, Italy. E-mail address: [email protected]. 0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.08.007

(FDA), outlined that the risk of rhabdomyolysis and other adverse effects from statin use can be compounded by other factors including altered renal and hepatic functioning, hypothyroidism, and concomitant medications.5 Most of the 3,399 cases of statin-associated myopathy that were reported were linked to a combination with some class of drugs.5 The main classes of drugs responsible for interaction with statins were fibrates (gemfibrozil), cyclosporine, erythromycin, clarithromycin, warfarin, digoxin, and some antifungals (Table 4).5 The reason for potential interaction with statins can be attributed to pharmacokinetics, many of which are related to the CYP3A4 that is responsible for the metabolism of many of these classes of drugs. Differences in biotransformation can affect the potential for drug interactions with statins. All statins (except pravastatin) undergo extensive microsomal metabolism by the CYP450 isoenzyme systems.2 Lovastatin, simvastatin, and atorvastatin are biotransformed in the liver primarily by the CYP3A4 system, whereas fluvastatin is metabolized primarily by the CYP2C9 enzyme along with CYP3A4 and CYP2C8 to a lesser extent; rosuvastatin is not extensively metabolized, but it does have some interaction with the CYP2C9 enzyme.2 As a result of these differences, a number of drugs may increase the risk of myopathy and rhabdomyolysis when used concomitantly with statins (Table 5). Until recently, the mechanism by which fibrates may increase the risk of myopathy has not been fully understood. Both statins and fibrates have been reported to cause myopathy; therefore both drugs taken together may potentiate the likelihood of myotoxicity.4 The interaction between statins and fibrates was considered a class effect for fibrates until recent pharmacokinetic and mechanistic studies demonstrated the pharmacologic differences between gemfibrozil and fenofibrate, specifically different routes of metabolism that have significant clinical relevance when combination therapy with statins and other drugs is administered.3 Transporters are classes of proteins involved in drug disposition present in different tissues.6 All statins are recognized by transporters. The organic anion transporting polypeptides in the liver mediate the uptake of many organic anions, including www.AJConline.org

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Table 1 Pharmacokinetic properties of statins

Absorption (%) Bioavailability (%) Half-life (hr) Protein binding (%)

Simvastatin

Pravastatin

Fluvastatin

Atorvastatin

Cerivastatin

Rosuvastatin

Lovastatin

60–80 5 2 95

34 20 1–3 50

⬎90 30 1 ⬎98

30 12 14 ⬎98

⬎98 60 2–3 ⬎99

50 20 21 88

30 5 5 ⬎95

CYP ⫽ cytochrome P450. Adapted from Pharmacol Ther1,1a and Circulation.2

Table 2 Clinical pharmacokinetics of statins (mechanisms of metabolism) Parameter

Atorva

Rosuva

Fluva

Fluva XL

Lova

Prava

Simva

Hepatic extraction (%) Metabolism

⬎ 70 CYP3A4

⬎ 68 CYP2C9

⬎ 68 CYP2C9

⬎ 70 CYP3A4

46–66 Sulfation

78–87 CYP3A4

Systemic metabolites Clearance (mL/min) ClR (mL/min)

Active 291.6 —

63 Biliar CYP2C9, 2C19 (minor) Active (minor) 805 226

Inactive 1,131.6 —

Inactive 4,433 —

Active 303–1,166 —

Inactive 945 ⬎400

Active 525 —

Atorva ⫽ atorvastatin; ClR ⫽ renal clearance; CYP ⫽ cytochrome P450; Fluva ⫽ fluvastatin; Lova ⫽ lovastatin; Prava ⫽ pravastatin; Rosuva ⫽ rosuvastatin; Simva ⫽ simvastatin. Adapted from Circulation.2

Figure 1. Metabolic pathways of statins. CoASH ⫽ coenzyme ASH; P450s ⫽ cytochrome P450s; UG7 ⫽ uridine diphosphate– glucuronosyl transferase. (Reprinted with permission from Drug Metab Dispos.3)

statins.6 Interaction between gemfibrozil and statins may result from interaction with transporters in the liver, either due to the reduced hepatocyte uptake by transporters or by a reduced biliary secretion.6 Polymorphism of

the protein transporters also may affect statin activity and is another factor to be considered in addressing the role of these transporters in terms of lipid-lowering activity and drug safety.

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Both fenofibrate and gemfibrozil are similar with regard to metabolism via glucuronidation and renal excretion (Table 6); however, they differ significantly in that they use different families of the hepatic glucuronidation enzymes (uridine diphosphate– glucuronosyltransferase [UGT] 1A9 and UGT2B7 for fenofibrate and UGT1A1 and UGT1A3 for gemfibrozil). These differences have significant clinical implications because most statins are glucuronidated by the same family of enzymes as gemfibrozil, thereby competing for conversion of statins from the open form to lactone form, which undergoes liver metabolism catalyzed by cytochrome (Figure 1). In addition, although fenofibrate is only a mild inhibitor of CYP2C9, gemfibrozil is a potent inhibitor of CYP2C9 and CYP2C8.7 Altogether, many mechanisms on a pharmacokinetic basis are responsible for the interaction between gemfibrozil and any statins. In addition, many drugs for treating diabetes mellitus, such as rosiglitazone, pioglitazone, repaglimide, and glimepiride are metabolized by CYP2C8, and individuals with diabetes frequently require a fibrate for the treatment of dyslipidemia.8 –11 Therefore, the likelihood of a drug interaction with gemfibrozil in patients taking diabetic medications is very high. Support for statin-fibrate combination therapy is found in both the American Diabetes Association (ADA)12 and the National Institute of Clinical Excellence (NICE) guidelines.13 The UK High-Density Lipoprotein Cholesterol (HDL-C) Consensus Group acknowledges the role of fibrates in reducing coronary risk, particularly in patients with features of the metabolic syndrome.14 However, the combination of statins with gemfibrozil has resulted in cases of severe myopathy, and use of this combination therapy only after assessing risk versus benefits has been recommended.15,16 There is compelling evidence that the combination of fenofibrate with a statin has a significantly greater safety profile than the combination of gemfibrozil with a statin.16 Gemfibrozil, but not fenofibrate, has been demonstrated to cause a significant increase in the statin area under the concentration time curve (AUC). In addition, statin myopathy has been shown to be directly related to dosage or when combined with drugs that interfere with statin metabolism, resulting in an increase in the AUC.4

Differences in Safety Experience Between Gemfibrozil and Fenofibrate As monotherapy, both statins and fibrates have been reported to cause myopathy. An enhanced risk of myopathy with the combined use of a statin and a fibrate therefore is not unexpected. There have been numerous published reports on gemfibrozil-statin–associated rhabdomyolysis (Table 7).16a However, cases of fenofibrate-associated myopathy, either as monotherapy or in combination, appear to be exceedingly rare.17–26 There are also reports documenting cases of myopathy when therapy was switched from a

Table 3 Clinically relevant drug interactions with statins Drug

Atorva

Ceriva

Fluva

Lova

Prava

Simva

Warfarin Digoxin Nicotinic acid Erythromycin Cyclosporine Fibrates Azole antifungals

⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫹

⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫺

⫹ ⫹ ⫺ ⫺ ⫺ ⫹ ⫺

⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹

⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺

⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹

Atorva ⫽ atorvastatin; Ceriva ⫽ cerivastatin; Fluva ⫽ fluvastatin; Lova ⫽ lovastatin; Prava ⫽ pravastatin; Simva ⫽ simvastatin; ⫹ ⫽ interaction reported; ⫺ ⫽ no interaction reported. Adapted from Arch Intern Med.4

Table 4 Percentage of cases associated with concomitant medications affecting statin metabolism Agent

Percentage

Mibefradil Fibrates Cyclosporine Macrolide antibiotics Warfarin Digoxin Azole antifungals Total

2% 38% 4% 3% 4% 5% 1% 57%

Adapted from JAMA.5

Table 5 Selected drugs that may increase risk of myopathy and rhabdomyolysis when used concomitantly with statins CYP3A4 Inhibitors/Substrates

Others

● Macrolides (azithromycin, clarithromycin, erythromycin) ● Azole antifungals (itraconazole, ketoconazole) ● Calcium antagonists (mibefradil, diltiazem, verapamil) ● Nefazodone ● Protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir) ● Sildenafil ● Warfarin

● Digoxin ● Fibrates (gemfibrozil) ● Niacin

CYP ⫽ cytochrone P450. Adapted from Pharmacol Ther.1

combination of a statin with fibrate to a statin with gemfibrozil or bezafibrate.27,28 Evaluations of the pharmacoepidemiologic reports of rhabdomyolysis also have demonstrated a notable difference in the reporting rates for gemfibrozil compared with fenofibrate. The FDA Adverse Event Report (AER) database evaluations have demonstrated a substantially lower rate of rhabdomyolysis in patients taking fenofibrate than in those taking gemfibrozil, even when greater use of gemfibrozil in clinical practice was taken into consideration.29,30

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Table 6 Pharmacokinetic properties of gemfibrozil and fenofibrate Pharmacokinetic Parameter

Gemfibrozil

Fenofibrate (Micronized)

Major metabolic pathway Effect on oxidative metabolism via CYP isoenzymes Route of elimination Half-life (hr) Protein binding Effect of food on absorption

Glucuronidation Data inconsistent

Bioavailability Dose reduction in renal impairment

100% CrCl 10–15 mL/min, reduce dose by 50%

Glucuronidation Weak inhibitor of CYP2C19, CYP2A6, mild-to-moderate inhibitor of CYP2C9 Renal 19–27 99% Extent of absorption is increased by 35% under fed vs fasted conditions Nearly 100% (micronized) CrCl ⬍50 mL/min, reduce dose

Renal 1.3 98% NA

CrCl ⫽ creatinine clearance; CYP ⫽ cytochrome P450; NA ⫽ not available. Adapted from US Department of Veterans Affairs Statin Fibrate Safety Report.33 Table 7 US Food and Drug Administration Adverse Event Reporting System rate for statin-associated cases of rhabdomyolysis monotherapy versus combination* Lovastatin Cases per 100,000 Rx for monotherapy Cases per 100,000 Rx for combination therapy Relative increase

0.12 284 24⫻

Pravastatin

Simvastatin

Fluvastatin

Atorvastatin

0.02

0.08

0

0.03

0.14

3.85

0

0.5

0

17⫻

7⫻

48⫻

Cerivastatin 1.81 1,248 690⫻

Rx ⫽ prescriptions. * Combination statin-gemfibrozil therapy. Adapted from Pharmacoepidemiol Drugs.16a

When given in combination with any statin medication, fenofibrate resulted in fewer reports of rhabdomyolysis than gemfibrozil. Only 2.3% (14 of 606) of the total number of reports of rhabdomyolysis with fenofibrate and statin therapies was associated with fenofibrate-cerivastatin combination therapy versus 88% (533 of 606) associated with gemfibrozilcerivastatin therapy. Similarly, the number of reports of rhabdomyolysis per million prescriptions dispensed was approximately 33 times lower with fenofibrate than with gemfibrozil when used in combination with cerivastatin.29 When given in combination with any statin other than cerivastatin, fenofibrate use was also associated with a lower reporting rate of rhabdomyolysis. Additionally, the number of reports of rhabdomyolysis per million prescriptions dispensed was approximately 15 times lower for fenofibrate than for gemfibrozil, with 0.58 reports per million prescriptions dispensed for fenofibrate versus 8.6 reports for gemfibrozil.29 Results from a second analysis of the FDA AER database revealed 59.6 cases of rhabdomyolysis per million prescriptions of gemfibrozil versus 5.5 per million prescriptions for fenofibrate. Because the reporting of adverse events tends to be greater with newly marketed drugs such as fenofibrate, the rate of fenofibrate AERs in both of these analyses may have been exaggerated when compared with those of gemfibrozil, which has been in use for a longer period. Data from an analysis from 11 managed care health plans in which prescription data were matched with claims data on

hospitalizations between January 1, 1998 and June 30, 2001 indicated that cerivastatin, combined with a fibrate, conferred a risk of hospitalization for rhabdomyolysis of approximately 1 in 10 treated patients per year. Of 12,695 patients taking cerivastatin, 4 taking monotherapy and 6 taking a combination with gemfibrozil developed rhabdomyolysis.31 No patient taking fenofibrate and cerivastatin combination therapy was reported to have developed rhabdomyolysis. In this evaluation of 252,460 patients on lipid-lowering therapies, of the 24 cases of rhabdomyolisis, only 1 patient was taking fenofibrate. This patient was also taking 40 mg of atorvastatin. (There also were 7 cases of rhabdomyolysis in patients taking atorvastatin as monotherapy). Additional data from a US Department of Veterans Affairs database evaluation (October 1, 2002 to September 30, 2003) demonstrated that there were 93,677 patients taking a combination of gemfibrozil and a statin, and 1,830 patients taking fenofibrate with a statin. In that period, there were 149 cases of rhabdomyolysis or acute tubular necrosis in the 93,677 patients taking gemfibrozil with any statin, for an overall rate of 0.16%. Of note, there were no cases of rhabdomyolysis or acute tubular necrosis in 1,830 patients taking fenofibrate with any statin.17 Additional support for the safety of fenofibrate in combination with cerivastatin is seen in the Lipids in Diabetes Study (LDS),32 which enrolled ⬎2,000 patients taking combined cerivastatin 0.4 mg with minimized fenofibrate 200 mg for up to 1 year. Although the study was discontinued in

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Table 8 Kinetic parameters of statins coadministered with gemfibrozil or fenofibrate Statin

Cmax, with/without gemfibrozil (ng/mL)

Ratio

AUC, with/without gemfibrozil (ng · hr/mL)

Ratio

Cmax, with/without fenofibrate (ng/mL)

Ratio

AUC, with/without fenofibrate (ng · hr/mL)

Ratio

Reference

Lovastatin acid Simvastatin acid Pravastatin Fluvastatin Cerivastatin Rosuvastatin Atorvastatin

7.80/2.78 3.2/6.8 120/66.3 54.3/48.4 8.0/3.2 109/49.5 NA

2.80 2.11 1.81 1.12 2.5 2.20 NA

77.9/27.9 20/58.2 NA 213/227 91.1/20.9 771/410 NA

2.79 2.33 NA 0.938 4.36 1.88 NA

NA 43.1/42.8 NA 8.19/7.49 NA NA NA

NA 0.99 1.36 0.91 1.30 0.96 NA

NA 166.7/190 NA 144.6/139 NA NA NA

NA 0.88 1.39 0.96 0.98 1.07 0.83

6, 35 36, 37 38, 39 40, 41 42, 43 44, 45 39

AUC ⫽ area under the curve; Cmax ⫽ maximum concentration of drug; NA ⫽ not available. Adapted from Annu Rev Pharmacol Toxicol.6

August 2001 with the withdrawal of cerivastatin, there were no cases of myositis or rhabdomyolysis in the patient cohort taking the combination of fenofibrate and cerivastatin. Similarly, in the Simvastatin Plus Fenofibrate for Combined Hyperlipidemia (SAFARI) trial,33 which enrolled 411 patients to simvastatin 20 mg and fenofibrate 160 mg combination therapy, no patient developed myopathy. In light of the increasing prevalence of the metabolic syndrome and diabetes, and evidence that these patient populations have a high residual risk of CAD events even with statin therapy, the clinical use of a statin and a fibrate is likely to increase.7

Conclusion The role of statin-fibrate therapy is a recognized approach to targeting risk reduction in patients with dyslipidemia, particularly those with the metabolic syndrome. Ultimately, combination statin-fibrate therapy often may be required to control all lipid abnormalities, such as in patients with the metabolic syndrome, because fibrates provide additional benefits, particularly with respect to triglycerides and HDL cholesterol levels.34 Consideration of specific aspects of statin metabolism should be carefully considered to predict drug interactions, which is an important determinant of safety during long-term therapy. There is compelling evidence that the combination of fenofibrate with a statin has a significantly greater safety profile than the combination of gemfibrozil with a statin. Three lines of evidence support this conclusion. First, gemfibrozil, but not fenofibrate, causes a 2- to 6-fold increase in the statin AUC (Table 8).35– 45 Statin myopathy has been shown to be directly related to dosage or when combined with drugs that interfere with statin metabolism, resulting in an increase in the AUC. Second, the FDA AER database, after correcting for prescription use, demonstrates that the rate of rhabdomyolysis for gemfibrozil is 10- to 15-fold higher than for fenofibrate when given in combination with a statin. An analysis of managed care databases also suggests a much lower rate of hospitalization in patients with rhabdomyolysis taking

fenofibrate than in those taking gemfibrozil. Finally, clinical trial data from the LDS and the SAFARI trial, which together enrolled ⬎2,500 patients taking a statin with fenofibrate, reported no cases of myopathy. Small trials with a combination of gemfibrozil and statins have demonstrated about a 5% rate of myopathy.46 Another important safety concern regarding the use of gemfibrozil is the interaction with drugs that are metabolized by CYP2C8. Gemfibrozil as a potent inhibitor of CYP2C8 increases the AUC significantly for many of the more recently approved drugs for the treatment of diabetes such as rosiglitazone, pioglitazone, repaglanide, and glyburide. Regulatory authorities have warned physicians about the increased risk of hypoglycemia from the combination of gemfibrozil with repaglinide. Fenofibrate is not an inhibitor of CYP2C8, and does not adversely affect the pharmacokinetics of repaglinide. In light of the increasing prevalence of the metabolic syndrome and diabetes, and evidence that these patient populations have a high residual risk of CAD events even on statin therapy, the clinical use of a statin and a fibrate is likely to increase. Safety concerns regarding the combination of a statin and a fibrate have forced clinicians to administer this combination of lipid-altering therapy with caution. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is a 10,000-patient trial evaluating the CAD benefits of adding fenofibrate to simvastatin in diabetes.47 This trial is due to be completed in 2009. Meanwhile, for patients who may benefit from a combination of a statin and a fibrate, fenofibrate (based on considerable evidence) should be the preferred option to provide the patient with the maximal benefit–risk ratio. 1. Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins [published correction appears in Pharmacol Ther 2000; 86:199.] Pharmacol Ther 1999;84:413– 428. 1a.Christians U, Jacobsen W, Floren LC. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar? Pharmacol Ther 1998;80:1–34.

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