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Atorvastatin

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Atorvastatin
Clinical data
Pregnancy
category
  • AU: D
Routes of
administration		oral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability12%
MetabolismHepatic - CYP3A4
Elimination half-life14 hours
ExcretionBile
Identifiers
  • (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.125.464 Edit this at Wikidata
Chemical and physical data
FormulaC33H35FN2O5
Molar mass558.64 g·mol−1
3D model (JSmol)
  • O[C@H](CCn1c(c2ccc(F)cc2)c(c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C)C[C@@H](O)CC(=O)O

Atorvastatin (INN) (Template:PronEng) (Lipitor, Pfizer), is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms.

Atorvastatin inhibits HMG-CoA reductase, the rate-determining enzyme located in hepatic tissue that produces mevalonate, a small molecule used in the synthesis of cholesterol and other mevalonate derivatives. This lowers the amount of cholesterol produced which in turn lowers the total amount of LDL cholesterol.

Atorvastatin was first synthesized in 1985 by Bruce Roth while working at Parke-Davis Warner-Lambert Company (now Pfizer).

With 2006 sales of US$12.9 billion, Lipitor is the largest-selling drug in the world.[1]

Lipitor is not the only statin; there are several other statins on the market.[2][3]

Pharmacology

Main article: Statin

As with other statins, and 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.

In clinical trials, adding ezetimibe (Zetia) to Lipitor lowered cholesterol more effectively than Vytorin (ezetimibe + simvastatin). [citation needed]

Pharmacokinetics

Atorvastatin has rapid oral absorption with an approximate time to maximum plasma concentration (Tmax) of 1-2 hours. The absolute bioavailability of atorvastatin is approximately 14%, however, 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. Food has shown to reduce the rate and extent of atorvastatin absorption. Administration of atorvastatin with food produces a 25% reduction in Cmax (rate of absorption) and a 9% reduction in AUC (extent of absorption). However, food does not affect the plasma LDL-C lowering efficacy of atorvastatin. Evening atorvastatin dose administration is known to reduce the Cmax (rate of absorption) and AUC (extent of absorption) by 30% each. However, time of administration does not affect the plasma LDL-C lowering efficacy of atorvastatin.

Atorvastatin is highly protein bound (≥98%) with a blood/plasma concentration ratio of 0.25 indicating a low red blood cell distribution.

The primary proposed mechanism of atorvastatin metabolism is 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 CYP 3A4 to produce increased or decreased plasma concentrations, respectively. This interaction was tested in vitro with concurrent administration of erythromycin, a known CYP 3A4 isozyme inhibitor, which resulted in increased plasma concentrations of atorvastatin. Atorvastatin is also an inhibitor of cytochrome 3A4.

It is primarily eliminated via hepatic biliary excretion with less than 2% of atorvastatin recovered in the urine. Bile elimination follows hepatic and/or extra-hepatic metabolism. There does not appear to be any entero-hepatic recirculation. Atorvastatin has an approximate elimination half-life of 14 hours. Noteworthy, the HMG-CoA reductase inhibitory activity appears to have a half-life of 20-30 hours, 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[4].

In Hepatic insufficiency, Plasma drug concentrations are significantly affected by concurrent liver disease. Patients with A stage liver disease show a 4-fold increase in both Cmax and AUC. Patients with B stage liver disease show an 16-fold increase in Cmax and an 11-fold increase in AUC.

In Geriatric patients (>65 years old) show altered pharmacokinetics of atorvastatin compared to young adults. The mean AUC and Cmax values are higher (40% and 30%, respectively) for geriatric patients. Additionally, healthy elderly patients show a greater pharmacodynamic response to atorvastatin at any dose, therefore, this population may have lower effective doses[5].

Clinical use

FDA Approved Indications

  • Concomitant Therapy Considerations
Atorvastatin may be used in combination with bile acid resins. It is not recommended to combine statin treatment with fibrates because of the increased risk of myopathy related adverse reactions[5].Drug dose must be adjusted according to age of patient, and must be lowered in Hepatic insufficiency

Contraindications

Precaution must be taken when treating with atorvastatin, because rarely it may lead to rhabdomyolysis [20], 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.[4]. Also Atorvastatin should be discontinued if a patient has markedly elevated CPK levels or if a myopathy is suspected or diagnosed. The likelihood of developing a myopathy is increased by the co-administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, and azole antifungals[5]

Atorvastatin is absolutely contraindicated in pregnancy, it is likely to cause harm to fetal development because of the importance of cholesterol and various products in the cholesterol biosynthesis pathway for fetal development, including steroid synthesis and cell membrane production. It is not recommended that nursing mothers take atorvastatin due to the possibility of adverse reactions in nursing infants, since experiments with rats indicate that atorvastatin is likely to be secreted into human milk[5].

Drug and Food 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[21][22][23].

Co-administration of Atrovastatin with one of CYP3A4 inhibitors like itraconazole[24], 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 like diltiazem, erythromycin, fluconazole, ketoconazole, clarithromycin, cyclosporine, protease inhibitors, verapamil[25]. And only rearly with other CYP3A4 inhibitors like amiodarone, and aprepitant[4].often bosentan, fosphenytoin, and phenytoin which are CYP3A4 inducers can decrease the plasma concentrations of atorvastatin.But only rarely barbiturates, carbamazepine, efavirenz, nevirapine, oxcarbazepine, rifampin, and rifamycin[26], which are 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. [27]

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

Niacin also is proved to increase the risk of myopathy or rhabdomyolysis[4]

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.[4]

Vitamin D supplementation lowers atorvastatin and active metabolite concentrations yet has synergistic effects on cholesterol concentrations[28].Grapefruit juice components are known inhibitors of intestinal CYP3A4.Co-administration of grapefruit juice with atorvastatin may cause an increase in Cmax and AUC, which can lead to adverse reactions or overdose toxicity[29]

Available forms

Pack and tablet of Atorvastatin (Lipitor) 40mg

Atorvastatin calcium tablets are currently marketed by Pfizer under the trade name Lipitor, in tablets (10, 20, 40 or 80 mg) for oral administration. Tablets are white, elliptical, and film coated. Pfizer also packages the drug in combination with other drugs, such as is the case with its Caduet. In some countries, atorvastatin calcium is made in tablet form by generic drug makers under various brand names including Atoris, Atorlip, Lipvas, Sortis, Torvast, Torvacard, Totalip, and Tulip.

Adverse effects

As stated earlier, myopathy with elevation of creatinine kinase (CK)[30] and rhabdomyolysis are the most serious, although rare <1%.[12][5]

  • Headache is the most common side effect, occurring in more than 10% of patients.

Side effects that occur in 1-10% of patients taking atorvastatin include:

Elevation of alanine transaminase (ALT) and aspartate transaminase (AST) has been described in a few cases[31][4]

Other very rare side effects occurring in less than 1% of patients are: alopecia, anaphylaxis, angina, angioneurotic edema, arrhythmia, bullous rashes, cholestatic jaundice, deafness, dyspnea, erythema multiforme, esophagitis, facial paralysis, glaucoma, gout, hepatitis, hyperkinesia, impotence, migraine, myasthenia, myositis, nephritis, pancreatitis, paresthesia, peripheral neuropathy, petechiae, photosensitivity, postural hypotension, pruritus, rectal hemorrhage, rhabdomyolysis, somnolence, Stevens-Johnson syndrome, syncope, tendinous contracture, thrombocytopenia, tinnitus, torticollis, toxic epidermal necrolysis, urticaria, vaginal hemorrhage, and vomiting[5].

Market

Lipitor Market analysis

In 2006, Pfizer’s Lipitor (atorvastatin) generated global revenues of $13.6bn, making it the best selling drug in pharmaceutical history. The blockbuster medicine has single-handedly driven the overall revenue margins of the cardiovascular segment, as this area continues to dominate the pharmaceutical market.
However, as Lipitor’s blockbuster revenue is seriously threatened by imminent patent expiration in some of the drug’s largest markets such as the US, Japan and the UK, there is significant unrest between Pfizer’s key stakeholders about the future of the drug.

Patent challenge

The size of the market for atorvastatin has prompted the generic drug manufacturing company Ranbaxy to challenge the validity of some of Pfizer's patents in patent courts across the world. As of March 2007, courts had mostly upheld the validity of Pfizer's original patent for atorvastatin, which is due to expire in European territories in 2011 (but 2010 in Canada). However a later patent for the specific enantiomer of the atorvastatin formula that is medically useful, which would have given Pfizer longer protection, has fared less well. Although upheld in the United States[32], Spain, and Ecuador, the enantiomer patent has been declared invalid by courts in Malaysia, Austria, Australia, Canada, the Netherlands and the United Kingdom[33].

Pfizer fight against simvastatin alternative

After doctors and patients began switching by the millions to a cheaper alternative within the same class of drugs called simvastatin, Pfizer launched a campaign including advertisements, lobbying efforts, and a paid speaking tour by Dr. Louis W. Sullivan, a former secretary of the federal Department of Health and Human Services, to discourage the trend.[2] The main clinical advantage of Lipitor over Simvastatin is that it is not metabolised by certain liver enzymes, and thus its blood concentration is not increased when combined with grapefruit juice which inhibits these enzymes. Simvastatin patients should avoid drinking large amounts of grapefruit juice for this reason. An independent analysis showed that, at commonly prescribed doses, atorvastatin and simvastatin have no statistically significant differences in reducing cardiovascular morbidity and mortality.[34]

Advertisements withdrawn

On February 25, 2008, Pfizer announced that it will voluntarily withdraw all advertisements for Lipitor featuring Dr. Robert Jarvik and will commit to ensuring greater clarity in the roles and responsibilities of its spokespeople in its consumer advertising and promotion. [35] Dr. Jarvik is not a licensed physician and his use in advertisements was considered misleading. In addition, although he was shown rowing (and therefore implying that his heart was healthy) he in fact does not row and the advertisement employed a body double. Pfizer withdrew the advertisement as a result of bad press.[citation needed]

References

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Further reading

Retrieved from "https://en.wikipedia.org/enwiki/w/index.php?title=Atorvastatin&oldid=291173761"