Atorvastatin

Atorvastatin (INN)

Systematic (IUPAC) name
(3R,5R)-7-[2-(4-Fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid
Clinical data
Pronunciation	/əˌtɔːrvəˈstætən/
Trade names	Lipitor, Atorva
AHFS/Drugs.com	monograph
MedlinePlus	a600045
Licence data	US Daily Med:link
Pregnancy category	AU: D US: X (Contraindicated)
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	12%
Metabolism	Hepatic - CYP3A4
Biological half-life	14 h
Excretion	Bile
Identifiers
CAS Number	134523-00-5 Y
ATC code	C10AA05 (WHO)
PubChem	CID: 60823
IUPHAR/BPS	2949
DrugBank	APRD00055 N
ChemSpider	54810 Y
UNII	A0JWA85V8F N
KEGG	D07474 Y
ChEBI	CHEBI:39548 Y
ChEMBL	CHEMBL1487 Y
PDB ligand ID	117 (PDBe, RCSB PDB)
Chemical data
Formula	C33H35FN2O5
Molecular mass	558.64
SMILES O=C(O)C[C@H](O)C[C@H](O)CCn2c(c(c(c2c1ccc(F)cc1)c3ccccc3)C(=O)Nc4ccccc4)C(C)C
InChI InChI=1S/C33H35FN2O5/c1-21(2)31-30(33(41)35-25-11-7-4-8-12-25)29(22-9-5-3-6-10-22)32(23-13-15-24(34)16-14-23)36(31)18-17-26(37)19-27(38)20-28(39)40/h3-16,21,26-27,37-38H,17-20H2,1-2H3,(H,35,41)(H,39,40)/t26-,27-/m1/s1 Y Key:XUKUURHRXDUEBC-KAYWLYCHSA-N Y
NY (what is this?)  (verify)

Atorvastatin, marketed under the trade name Lipitor among others, is a member of the drug class known as statins, which are used primarily for lowering blood cholesterol and for prevention of events associated with cardiovascular disease. Like all statins, atorvastatin works by inhibiting HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body.

The synthesis of atorvastatin took place on August 1985 at Warner-Lambert's Parke-Davis Pharmaceutical Research facility in Ann Arbor, Michigan. by Bruce Roth, leading a team of 18 scientists researching atherosclerosis. From 1996 to 2012 under the trade name Lipitor, atorvastatin became the world's best-selling drug of all time, with more than US$125 billion in sales over approximately 14.5 years.

Medical uses

The primary uses of atorvastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease:

Dyslipidemia

• Hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb) to reduce total cholesterol, LDL-C, apo-B, triglycerides levels, and CRP as well as increase HDL levels.
• Heterozygous familial hypercholesterolemia in pediatric patients
• Homozygous familial hypercholesterolemia
• Hypertriglyceridemia (Fredrickson Type IV)
• Primary dysbetalipoproteinemia (Fredrickson Type III)
• Combined hyperlipidemia

Cardiovascular disease

• Primary prevention of heart attack, stroke, and need for revascularization procedures in patients who have risk factors such as age, smoking, high blood pressure, low HDL-C, and a family history of early heart disease, but have not yet developed clinically evident coronary heart disease.
• Secondary prevention of myocardial infarction, stroke, unstable angina, and revascularization in people with established coronary heart disease.
• Myocardial infarction and stroke prophylaxis in patients with type II diabetes

Other uses

There have been recent studies suggesting that high-dose statin therapy plays a plaque-stabilizing role in patients suffering from acute coronary syndrome and thrombotic stroke.

Administration

Atorvastatin may be used in combination with bile acid sequestrants and ezetimibe to increase the reduction in cholesterol levels. However, It is not recommended to combine statin drug treatment with certain other cholesterol-lowering drugs, particularly fibrates, because this may increase the risk of myopathy-related adverse effects.

While many statin medications should be administered at bedtime for optimal effect, atorvastatin can be dosed at any time of day, as long as it is continually dosed once daily at the same time.

Specific populations

• Geriatric: Plasma concentrations of atorvastatin in healthy elderly subjects are higher than those in young adults, and clinical data suggests a greater degree of LDL-lowering at any dose for patients in the population as compared to young adults.
• Pediatric: Pharmacokinetic data is not available for this population.
• Gender: Plasma concentrations are generally higher in women than in men, but there is no clinically significant difference in the extent of LDL reduction between men and women.
• Renal impairment: Renal disease has no influence on plasma concentrations of atorvastatin and dosing need not be adjusted in these patients.
• Hemodialysis: Hemodialysis will not significantly alter drug levels or change clinical effect of atorvastatin.
• Hepatic impairment: In patients with chronic alcoholic liver disease, levels of atorvastatin may be significantly increased depending upon the extent of liver disease.

Contraindications

• Active liver disease: cholestasis, hepatic encephalopathy, hepatitis, and jaundice
• Unexplained elevations in AST or ALT levels
• Pregnancy: Atorvastatin may cause fetal harm by affecting serum cholesterol and triglyceride levels, which are essential for fetal development.
• Breastfeeding: Small amounts of other statin drugs have been found to pass into breast milk, although atorvastatin has not been studied, specifically.
• Markedly elevated CPK levels or if a myopathy is suspected or diagnosed after dosing of atorvastatin has begun. Very rarely, atorvastatin may cause rhabdomyolysis, and it may be very serious leading to acute renal failure due to myoglobinuria. If rhabdomyolysis is suspected or diagnosed, atorvastatin therapy should be discontinued immediately. The likelihood of developing a myopathy is increased by the co-administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, and azole antifungals.

Adverse effects

Major

• Myopathy with elevation of creatinine kinase (CK) and rhabdomyolysis are the most serious side effects, occurring rarely at a rate of 2.3 to 9.1 per 10,000 person-years among patients taking atorvastatin. As mentioned previously, atorvastatin should be discontinued immediately if this occurs.
• Persistent liver enzyme abnormalities occurred in 0.7% of patients who received atorvastatin in clinical trials. It is recommended that hepatic function be assessed with laboratory tests before beginning atorvastatin treatment and repeated as clinically indicated thereafter. If evidence of serious liver injury occurs while a patient is taking atorvastatin, it should be discontinued and not restarted until the etiology of the patient's liver dysfunction is defined. If no other cause is found, atorvastatin should be discontinued permanently.
• Diabetes mellitus type 2, an uncommon class effect of all statins.

Common

The following have been shown to occur in 1–10% of patients taking atorvastatin in clinical trials.

• diarrhea, dyspepsia, nausea
• Arthralgia, myalgia

High-dose atorvastatin have also been associated with worsening glycemic control.

Other

In 2014 the FDA reported memory loss, forgetfulness and confusion with all statin products including atorvastatin. The symptoms were not serious, rare and reversible on cessation of drug treatment.

Interactions

Interactions with clofibrate, fenofibrate, gemfibrozil, which are fibrates used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins, increase the risk of myopathy and rhabdomyolysis.

Co-administration of atorvastatin with one of CYP3A4 inhibitors such as itraconazole, telithromycin, and voriconazole, may increase serum concentrations of atorvastatin, which may lead to adverse reactions. This is less likely to happen with other CYP3A4 inhibitors such as diltiazem, erythromycin, fluconazole, ketoconazole, clarithromycin, cyclosporine, protease inhibitors, or verapamil, and only rarely with other CYP3A4 inhibitors, such as amiodarone and aprepitant. Often, bosentan, fosphenytoin, and phenytoin, which are CYP3A4 inducers, can decrease the plasma concentrations of atorvastatin. Only rarely, though, barbiturates, carbamazepine, efavirenz, nevirapine, oxcarbazepine, rifampin, and rifamycin, which are also CYP3A4 inducers, can decrease the plasma concentrations of atorvastatin. Oral contraceptives increased AUC values for norethindrone and ethinyl estradiol; these increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.

Antacids can rarely decrease the plasma concentrations of statin drugs, but do not affect the LDL-C-lowering efficacy.

Niacin also is proved to increase the risk of myopathy or rhabdomyolysis.

Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring.

Vitamin D supplementation lowers atorvastatin and active metabolite concentrations, yet synergistically reduces LDL and total cholesterol concentrations. Grapefruit juice components are known inhibitors of intestinal CYP3A4.

Co-administration of grapefruit juice with atorvastatin may cause an increase in C_max and AUC, which can lead to adverse reactions or overdose toxicity.

A few cases of myopathy have been reported when atorvastatin is given with colchicine.

Mechanism of action

Main article: Statin

As with other statins, atorvastatin is a competitive inhibitor of HMG-CoA reductase. Unlike most others, however, it is a completely synthetic compound. HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Like other statins, atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol.

Recent studies have shown that in patients suffering from acute coronary syndrome, high-dose statin treatment may play a plaque-stabilizing role. At high doses, statins have anti-inflammatory effects, incite reduction of the necrotic plaque core, and improve endothelial function, leading to plaque stabilization and, sometimes, plaque regression. However, there is an increased risk of statin-associated adverse effects with such high-dose statin treatment. There is a similar thought process and risks associated with using high-dose statins to prevent recurrence of thrombotic stroke.

Pharmacodynamics

The liver is the primary site of action of atorvastatin, as this is the principal site of both cholesterol synthesis and LDL clearance. It is the dosage of atorvastatin, rather than systemic drug concentration, which correlates with extent of LDL-C reduction.

Pharmacokinetics

Absorption

Atorvastatin undergoes rapid absorption when taken orally, with an approximate time to maximum plasma concentration (T_max) of 1–2 h. The absolute bioavailability of the drug is about 14%, but the systemic availability for HMG-CoA reductase activity is approximately 30%. Atorvastatin undergoes high intestinal clearance and first-pass metabolism, which is the main cause for the low systemic availability. Administration of atorvastatin with food produces a 25% reduction in C_max (rate of absorption) and a 9% reduction in AUC (extent of absorption), although food does not affect the plasma LDL-C-lowering efficacy of atorvastatin. Evening dose administration is known to reduce the C_max and AUC by 30% each. However, time of administration does not affect the plasma LDL-C-lowering efficacy of atorvastatin.

Distribution

The mean volume of distribution of atorvastatin is approximately 381 L. It is highly protein bound (≥98%), and studies have shown it is likely secreted into human breastmilk.

Metabolism

Atorvastatin metabolism is primarily through cytochrome P450 3A4 hydroxylation to form active ortho- and parahydroxylated metabolites, as well as various beta-oxidation metabolites. The ortho- and parahydroxylated metabolites are responsible for 70% of systemic HMG-CoA reductase activity. The ortho-hydroxy metabolite undergoes further metabolism via glucuronidation. As a substrate for the CYP3A4 isozyme, it has shown susceptibility to inhibitors and inducers of CYP3A4 to produce increased or decreased plasma concentrations, respectively. This interaction was tested in vitro with concurrent administration of erythromycin, a known CYP3A4 isozyme inhibitor, which resulted in increased plasma concentrations of atorvastatin. It is also an inhibitor of cytochrome 3A4.

Excretion

Atorvastatin is primarily eliminated via hepatic biliary excretion, with less than 2% recovered in the urine. Bile elimination follows hepatic and/or extrahepatic metabolism. There does not appear to be any entero-hepatic recirculation. Atorvastatin has an approximate elimination half-life of 14 h. Noteworthy, the HMG-CoA reductase inhibitory activity appears to have a half-life of 20–30 h, which is thought to be due to the active metabolites. Atorvastatin is also a substrate of the intestinal P-glycoprotein efflux transporter, which pumps the drug back into the intestinal lumen during drug absorption.

In hepatic insufficiency, plasma drug concentrations are significantly affected by concurrent liver disease. Patients with A-stage liver disease show a four-fold increase in both C_max and AUC. Patients with B-stage liver disease show a 16-fold increase in C_max and an 11-fold increase in AUC.

Geriatric patients (>65 years old) exhibit altered pharmacokinetics of atorvastatin compared to young adults, with mean AUC and C_max values that are 40% and 30% higher, respectively. Additionally, healthy elderly patients show a greater pharmacodynamic response to atorvastatin at any dose; therefore, this population may have lower effective doses.

Pharmacogenetics

Several genetic polymorphisms have been found to be associated with a higher incidence of undesirable side effects of atorvastatin. This phenomenon is suspected to be related to increased plasma levels of pharmacologically active metabolites, such as atorvastatin lactone and p-hydroxyatorvastatin. Atorvastatin and its active metabolites may be monitored in potentially susceptible patients using specific chromatographic techniques.

Chemical synthesis

Atorvastatin synthesis in commercial production (process) chemistry. The key step of establishing this drug's stereocenters, through initial use of an inexpensive natural product (chiral pool approach).

Atorvastatin synthesis during discovery chemistry. The key step of establishing stereocenters, using of a chiral ester auxiliary approach.

The first synthesis of atorvastatin at Parke-Davis that occurred during drug discovery was racemic followed by chiral chromatographic separation of the enantiomers. An early enantioselective route to atorvastatin made use of an ester chiral auxiliary to set the stereochemistry of the first of the two alcohol functional groups via a diastereoselective aldol reaction. Once the compound entered pre-clinical development, process chemistry developed a cost-effective and scalable synthesis. In atorvastatin's case, a key element of the overall synthesis was ensuring stereochemical purity in the final drug substance, and hence establishing the first stereocenter became a key aspect of the overall design. The final commercial production of atorvastatin relied on a chiral pool approach, where the stereochemistry of the first alcohol functional group was carried into the synthesis—through the choice of isoascorbic acid, an inexpensive and easily sourced plant-derived natural product.

History

Bruce Roth, who was hired by Warner-Lambert as a young chemist in 1982, had created an "experimental compound" codenamed CI 981 – later called atorvastatin – and moved it "from synthesis in 1985 into expensive clinical trials" when company executives began to balk at the cost. Roth's boss Roger Newton and Ronald Cresswell supported the young chemist's costly research but Warner-Lambert was concerned that atorvastatin was a me-too version of rival Merck & Co.'s orphan drug lovastatin (brand name Mevacor). Mevacor, which was first marketed in 1987, was the industry's first statin and Merck's synthetic version – Zocor – was in the advanced stages of development.

In 1994 the findings of a Merck-funded study were published in the The Lancet concluding the efficacy of statins in lowering cholesterol in 4444 Scandinavian patients proving for the first time not only that a "statin reduced “bad” LDL cholesterol but also that it led to a sharp drop in fatal heart attacks among patients with heart disease." In 1996 Warner-Lambert entered into a co-marketing agreement with Pfizer to sell Lipitor and in 2000 Pfizer acquired Warner-Lambert 2000 for $90.2 billion. Lipitor was on the market by 1996. By 2003 Lipitor had become the best selling pharmaceutical in the United States. From 1996 to 2012 under the trade name Lipitor, atorvastatin became the world's best-selling drug of all time, with more than $125 billion in sales over approximately 14.5 years. Lipitor alone "provided up to a quarter of Pfizer Inc.'s annual revenue for years."

Pfizer's patent on atorvastatin expired in November 2011.

Formulations

Pack and tablet of atorvastatin (Lipitor) 40mg

Atorvastatin calcium tablets are marketed by Pfizer under the trade name Lipitor for oral administration. Tablets are white, elliptical, and film-coated. Pfizer also packages the drug in combination with other drugs, such as with Caduet. Pfizer recommends that patients do not break tablets in half to take half-doses, even when this is recommended by their doctors.

Generic availability

Pfizer's U.S. patent on Lipitor expired on 30 November 2011. Initially, generic atorvastatin was manufactured only by Watson Pharmaceuticals and India's Ranbaxy Laboratories. Prices for the generic version did not drop to the level of other generics—$10 or less for a month's supply—until other manufacturers began to supply the drug in May 2012.

In other countries, atorvastatin calcium is made in tablet form by generic drug makers under various brand names including Stator, Atorvastatin Teva, Litorva, Torid, Atoris, Atorlip, Mactor, Lipvas, Sortis, Torvast, Torvacard, Totalip, and Tulip. Pfizer also makes its own generic version under the name Zarator, which is the sole Pharmac-subsidised brand of atorvastatin in New Zealand.

Drug recall

On 9 November 2012, Indian drugmaker Ranbaxy Laboratories Ltd. voluntarily recalled 10-, 20- and 40-mg doses of its generic version of atorvastatin in the United States. The lots of atorvastatin, packaged in bottles of 90 and 500 tablets, were recalled due to possible contamination with very small glass particles similar to the size of a grain of sand (less than 1 mm in size). The FDA received no reports of injury from the contamination.

External links

• Atorvastatin bound to proteins in the PDB
• Lipitor.com – manufacturer's site
• MedlinePlus Drug information: Atorvastatin (Systemic) – information from USP DI Advice for the Patient
• U.S. National Library of Medicine: Drug Information Portal - Atorvastatin