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STATINS: CLINICAL PHARMACOLOGY AND USE IN SPECIAL POPULATIONS

INTRODUCTION

Lipid-lowering drugs are among the most often-prescribed medications in the world. Since the late 1980s, HMG-CoA reductase inhibitors (commonly referred to as statins) have had an unprecedented impact on health care. In 2004, statins were among the top 200 best selling drugs, contributing close to $25 billion.¹ Nearly all cells possess the mevalonate pathway, which is the target of statin drugs. This pathway is linked to lipoprotein synthesis, electron transport, and cell proliferation via several intermediaries. Thus, the effects of statins are not restricted to the cardiovascular system. Statins work primarily by inhibiting peripheral cholesterol synthesis, which reduces the delivery of cholesterol to the liver. Consequently, low-density lipoprotein (LDL) receptor activity is upregulated, leading to enhanced clearance of LDL. Together, these effects reduce steady-state LDL levels. The potential differences between the individual drugs in this class are currently debated. This debate has led to a wider impression among clinicians that individual drug effects are more important than class effects.

CLINICAL PHARMACOLOGY

The 6 statins currently available for clinical use in the United States include the following (pitavastatin was approved for use in Japan in 2003):

1. Lovastatin - approved for use in 1987
2. Simvastatin - approved for use in 1991
3. Pravastatin - approved for use in 1991
4. Fluvastatin - approved for use in 1993
5. Atorvastatin - approved for use in 1996
6. Rosuvastatin - approved for use in 2004

HMG-CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis. It converts HMG-CoA to mevalonate. Statins target this enzyme and inhibit its activity. This mechanism was discovered in 1976, when Endo and Kuroda isolated a compound (ML-236A) from Penicillium citrinum that exhibited cholesterol-lowering effects in rats due to inhibition of HMG-CoA reductase.²

Affinity and efficacy of HMG-CoA reductase inhibitors

The affinity of statins for the enzyme HMG-CoA reductase is approximately 3 orders of magnitude higher than that of HMG-CoA. Earlier work with hepatic microsomal extracts in rats has shown that statins compete with the natural substrate for HMG-CoA reductase but not for NADPH.

Bioavailability of HMG-CoA reductase inhibitors

Most statins are primarily absorbed from the intestine and, to a lesser degree, from the stomach. Equivalent doses of different statins result in different distributions of the drug in the liver or peripheral tissues. Bioavailability varies from less than 5% (ie, pro drugs lovastatin, simvastatin) to 12-29% (ie, atorvastatin, pravastatin, rosuvastatin, fluvastatin). Absorption is highest (98%) for fluvastatin, mid-range (40-80%) for simvastatin and rosuvastatin, and lower (30-34%) for atorvastatin, lovastatin, and pravastatin. Timing the administration of lovastatin with a meal enhances the plasma concentration by 50%; however, dietary fiber may reduce its absorption. Administration of pravastatin with meals reduces its bioavailability by approximately 35%. Administration of fluvastatin with meals reduces its plasma concentration. Hepatic first-pass metabolism is significant (50-60%) with simvastatin; moderate (40-70%) with fluvastatin, lovastatin, pravastatin, and rosuvastatin; and lowest (20-30%) with atorvastatin. Once ingested, simvastatin, lovastatin, and atorvastatin are converted into active metabolites. For more details, see the Table.

COMBINATION THERAPY AND DRUG INTERACTIONS

Lovastatin, simvastatin, and atorvastatin are metabolized via cytochrome P450 (CYP) 3A4 pathway. Fluvastatin is metabolized by the 2CP pathway. Rosuvastatin and pravastatin are not significantly metabolized by the CYP pathway. Concomitant use of 2 drugs that are both metabolized via the CYP3A4 pathway results in competition for the pathway. This competition decreases the clearance of both drugs through the pathway, which leads to increased serum concentrations of both drugs. CYP3A4 inhibitors should be used with caution when prescribing lovastatin, simvastatin, or atorvastatin. Certain classes of drugs are notorious for serious interaction and deserve special mention.

Immunosuppressives
Cyclosporine significantly inhibits the CYP3A4 pathway and the prostaglandin P drug efflux pump system. It increases the area under the curve (AUC) for all statins, including pravastatin and rosuvastatin. It inhibits the organic anion transporter. All statins are ligands for this transporter. According to the results of the ALERT trial, fluvastatin might be the statin of choice in patients posttransplant.³

Antibiotics and antifungals
Erythromycin and ketoconazole are potent inhibitors of CYP3A4. Azithromycin, which does not affect the CYP3A4 system, may be a better choice when a short course of macrolide antibiotics is necessary for a patient also receiving statins. Alternatively, CYP3A4 statins should be temporarily suspended during the course of antibiotic therapy. Erythromycin does not seem to significantly affect the pharmacokinetics of pravastatin, rosuvastatin, and fluvastatin. Consequently, these statins may be relatively safer to use during erythromycin treatment. Use of lovastatin with antifungal drugs has been associated with myopathy. Pravastatin and rosuvastatin do not appear to affect itraconazole levels. Fluconazole might be safer to use concurrently with statins since it does not affect the CYP3A4 system.

Antidepressants
Fluoxetine, sertraline, nefazodone, and fluvoxamine inhibit CYP3A4 statin metabolism and must be used with caution. Paroxetine and venlafaxine do not affect the CYP3A4 system.

Protease inhibitors
Indinavir, nelfinavir, ritonavir, and saquinavir inhibit the CYP3A4 system. Of these, indinavir appears to be a less potent CYP3A4 inhibitor. Exercise caution when prescribing these drugs along with statins.

Anticoagulants
Warfarin is taken as a racemic mixture. R-warfarin (relatively weak anticoagulant) is primarily metabolized by CYP1A2, while the more potent S-warfarin is metabolized by the CYP2CP. All statins may affect the international normalized ratio (INR) in patients treated with statins.

Bile acid sequestrants
These can be used safely in combination with statins. However, they may reduce the plasma concentration of statins by 40-50% through delaying or decreasing absorption of orally administered statins.

Vitamins
Two percent of patients taking niacin (>1 g/d) with lovastatin experience myopathy. High doses of niacin may impair liver function, leading to increasing plasma statin concentration.

Fibrates (fibric acid derivatives)
Gemfibrozil use with statins results in increased risk of myopathy, including rhabdomyolysis. It inhibits glucuronidation of statins by uridine diphosphate (UDP) glucuronosyltransferase, which ordinarily promotes lactonization to inactive forms, increasing clearance. Fenofibrate appears to be a weaker inhibitor of this process and hence is relatively safe to use in combination with statins.

Grapefruit juice
Fresh or frozen grapefruit juice inhibits the intestinal CYP3A4 system. The primary factor responsible for this inhibition is a furanocoumarin compound 6’,7’-dihydroxybergamottin. The inhibitory effect is most pronounced with statins that undergo intestinal first-pass metabolism. Separating statin and grapefruit intake by at least 2 hours is perhaps prudent.

HMG-CoA REDUCTASE INHIBITORS IN SPECIAL POPULATIONS

Pregnant women
Pregnant women must not be prescribed statins.

Asians and other ethnic minorities
In the United States, African Americans, Hispanic Americans, and South Asians constitute large and growing minority populations. Generally, these ethnic groups have been underrepresented in large clinical trials, despite their considerably higher propensity to dyslipidemia, obesity, hypertension, and type 2 diabetes mellitus. Several studies that should shed more light on the efficacy and safety of statins in these populations are currently underway. One study conducted in 8 medical centers across 6 Asian countries reported achievement of the National Cholesterol Education Program (NCEP) LDL target goals in 81% of Asians taking 10 mg/d of atorvastatin or simvastatin.³ In Western nations, 27-59% of persons are reported to achieve this goal on 10 mg/d of atorvastatin, based on previously published data.⁴ However, a recent comparison of 2 studies (Getting to Appropriate LDL-C Levels with Simvastatin [GOALLS] and Simvastatin Treats Asians to Target [STATT]) demonstrated that Asians and non-Asians respond similarly to comparable doses of simvastatin.⁵ The GOALLS study was conducted in 33 centers across 17 countries; the STATT study was conducted in 5 Asian countries. This debate is far from over. Significant and intriguing differences were recently reported concerning the plasma exposure of rosuvastatin and its metabolites in Asians of Chinese, Malay, and Indian descent and whites.⁶

Children and adolescents with hyperlipidemia
Treating children with hyperlipidemia with statins is largely unexplored. NCEP guidelines suggest that statin treatment should be considered in members of this population aged 10 years or older if the LDL-C level is higher than 190 mg/dL or higher than 158 mg/dL in the presence of other cardiovascular risk factors, including positive family history of cardiovascular disease. Familial hypercholesterolemia (FH) is best diagnosed in children with LDL-C levels higher than 135 mg/dL and a family history of FH.

To date, approximately 666 children have been studied in various small (8 cases) and relatively larger (140 patients) series in which statins were used (simvastatin, lovastatin, pravastatin, and atorvastatin). These series included double-blind, randomized clinical trials. The mean LDL-C reduction reported ranged from 25% to 45%. The drugs were generally safe and well-tolerated when used in children and adolescents aged 8-18 years. The lowest dose used for pravastatin and simvastatin was 5 mg/d. The lowest dose for lovastatin and atorvastatin was 10 mg/d. The highest dose reported for any drug was 40 mg/d.⁷

References

1. Ansell, J: Making the Most of Statins: Risks and Benefits of Bringing Blockbusters into New Arenas. PharmaWeek [serial online]. Accessed December 8, 2005.
   
   
2. Endo A, Kuroda J: Citrinin, an inhibitor of cholesterol synthesis. J Antibiot (Tokyo), 1976;29(8)841-3.
   
   
3. Holdaas H, Fellstrom B, Jardine AG, et al: Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomized, placebo-controlled trial. Lancet 2003;361:2024-31.
   
   
4. Wu CC, Sy R, Tanphaichitr V, et al: Comparing the efficacy and safety of atorvastatin and simvastatin in Asians with elevated low-density lipoprotein-cholesterol—a multinational, multicenter, double-blind study. J Formos Med Assoc 2002;101:478-87.
   
   
5. Morales D, Chung N, Zhu JR, et al: Efficacy and safety of simvastatin in Asian and non-Asian coronary heart disease patients: a comparison of the GOALLS and STATT studies. Curr Med Res Opin 2004;20(8):1235-43.
   
   
6. Lee E, Ryan S, Birmingham B, et al: Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther 2005;78(4):330-41.
   
   
7. Rodenburg J, Vissers MN, Wiegman A, et al: Familial hypercholesterolemia in children. Curr Opin Lipidol 2004;15(4):405-11.

SUGGESTED FURTHER READING

Moghadasian MH: Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Life Sci 1999;65(13):132937.

Davidson M, Toth PP: Comparative effects of lipid-lowering therapies. Prog Cardiovasc Dis 2004:47(2):73-104.

Istvan E: Statin inhibition of HMG-CoA reductase: a 3-dimensional view. Atheroscler Suppl 2003;4(1):3-8.

Nemeroff CB, DeVane CL, Pollock BG: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996;153(3):311-20.

Miehalase EL: Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 1998;18(1):84-112.

Wiegman A, Hutten BA, de Groot E, et al: Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004;292(3):331-7.

Stein EA: Statins in children. Why and when. Nutr Metab Cardiovasc Dis 2001;5:24-9.

Rodenburg J, Vissers MN, Trip MD, et al: The spectrum of statin therapy in hyperlipidemic children. Semin Vasc Med 2004;4(4):313-20.

Tirona RG: Ethnic differences in statin disposition. Clin Pharmacol Ther 2005;78(4):311-6.