Atorvastatin was discovered by Bruce Roth and coworkers at Parke-Davis, since acquired by Warner-Lambert and then Pfizer. Although atorvastatin was the fifth drug in the class of statins to be developed, clinical trials showed that atorvastatin caused a more dramatic reduction in LDL-C than the other statin drugs. 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.
When Pfizer's patent on Lipitor expired on 30 November 2011, generic atorvastatin became available in the United States. Initially, atorvastatin was manufactured only by generic drugmakers 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 were able to supply the drug in May 2012.
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.
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.
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.
Myopathy with elevation of creatinine kinase (CK) and rhabdomyolysis are the most serious side effects, occurring rarely at a rate of <1% of patients taking atorvastatin. As mentioned previously, atorvastatin should be discontinued immediately if this occurs.
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.
The following have been shown to occur in 1–10% of patients taking atorvastatin in clinical trials:
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.
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.
Atorvastatin undergoes rapid absorption when taken orally, with an approximate time to maximum plasma concentration (Tmax) 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 Cmax (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 Cmax and AUC by 30% each. However, time of administration does not affect the plasma LDL-C-lowering efficacy of atorvastatin.
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.
Atorvastatin metabolism is primarily through cytochrome P4503A4hydroxylation 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.
Atorvastatin is primarily eliminated via hepaticbiliary 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 Cmax and AUC. Patients with B-stage liver disease show a 16-fold increase in Cmax 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 Cmax 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.
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.
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 diastereomers. 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.
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. When Pfizer's patent on Lipitor expired on 30 November 2011, generic Atorvastatin became available in the United States. In some 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.
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). Despite the contamination, the FDA received no reports of injury.
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