The wonderful lipid lowering drugs

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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):

Lovastatin - approved for use in 1987
Simvastatin - approved for use in 1991
Pravastatin - approved for use in 1991
Fluvastatin - approved for use in 1993
Atorvastatin - approved for use in 1996
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

Statins have been historically classified as Type I (fungally derived),
which includes lovastatin, simvastatin, and pravastatin; and Type II
(synthetic), which includes fluvastatin, atorvastatin, and rosuvastatin.
Another classification draws upon the lipophilicity (octanol solubility) or
hydrophilicity (water solubility) of the drugs. Pravastatin, rosuvastatin,
and fluvastatin are considered hydrophilic, to a limited extent. Lovastatin
and simvastatin are taken as pro drugs (lactone form) and subsequently
hydrolyzed to active metabolites (â-hydroxyl acid). Other statins are taken
in the active form (acid form).
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.

Table. Pharmacological Properties of Statins
Drug Form
(Pro Drug) Absorption, % Bioavailability, % Protein-Binding, % Plasma
Half-Life, hrs Renal
Clearance, % Tmax, hrs
Lovastatin Yes 30 <5 >95 1.1-1.7 <13 2-4
Pravastatin No 10-26 10-26 40-55 1.8-2 20 1-1.5
Simvastatin Yes 85 <5 >95 1.9-3.0 <13 1-3
Atorvastatin No 30 12-14 >98 14-15 <3 1-2
Fluvastatin No 98 29 >98 3 <6 0.6-1
Rosuvastatin No 40-60 20 88 20 10 3-5

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

Further studies are needed to assess the safety and efficacy of statins in
children of both genders and across all ethnic groups. The increase in
obesity and type 2 diabetes in children highlights the urgency of such
studies.
References

Ansell, J: Making the Most of Statins: Risks and Benefits of Bringing
Blockbusters into New Arenas. PharmaWeek [serial online]. Accessed December
8, 2005.


Endo A, Kuroda J: Citrinin, an inhibitor of cholesterol synthesis. J
Antibiot (Tokyo), 1976;29(8)841-3.


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.


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.


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.


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.


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.

Ferdinand KC: Managing cardiovascular risk in minority patients. J Natl Med
Assoc 2005;97(4):459-66.