Rosuvastatin
Encyclopedia
Rosuvastatin is a member of the drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

 class of statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...

s, used to treat high cholesterol
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...

 and related conditions, and to prevent cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...

. It was developed by Shionogi
Shionogi
is a Japanese pharmaceutical company best known for developing Crestor. Medical supply and brand name also uses Shionogi .Shionogi has business roots that date back to 1878, and was incorporated in 1919. Among the medicines produced are for hyperlipidaemia, antibiotics, and cancer medicines.In...

.

Medical uses

The primary uses of rosuvastatin is for the treatment of dyslipidemia
Dyslipidemia
Dyslipidemia or dyslipidaemia is an abnormal amount of lipids in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood, often due to diet and lifestyle. The prolonged elevation of insulin levels can lead to dyslipidemia...

. It is recommended to be used only after other measures such as diet, exercise, and weight reduction have not improved cholesterol levels.

Structure

Rosuvastatin has structural similarities with most other synthetic statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...

s, e.g., atorvastatin
Atorvastatin
Atorvastatin , sold by Pfizer under the trade name Lipitor, 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...

, cerivastatin
Cerivastatin
Cerivastatin is a synthetic member of the class of statins used to lower cholesterol and prevent cardiovascular disease. It was marketed by the pharmaceutical company Bayer A.G. in the late 1990s, competing with Pfizer's highly successful atorvastatin...

, pitavastatin
Pitavastatin
Pitavastatin is a member of the medication class of statins, marketed in the United States under the trade name Livalo. Like other statins, it is an inhibitor of HMG-CoA reductase, the enzyme that catalyses the first step of cholesterol synthesis. It has been available in Japan since 2003, and is...

, but rosuvastatin unusually also contains sulfur
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...

.

Crestor is actually rosuvastatin calcium, in which calcium replaces the H in the carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...

 group on the right of the 2 structure diagrams.

Mechanism of action

Rosuvastatin is a competitive inhibitor of the enzyme HMG-CoA reductase
HMG-CoA reductase
HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids...

, having a mechanism of action similar to that of other statins. Its approximate elimination half life is 19 hours and its time to peak plasma concentration is reached in 3–5 hours following oral administration.

Putative beneficial effects of rosuvastatin therapy on chronic heart failure may be negated by increases in collagen turnover markers as well as a reduction in plasma coenzyme Q10 (CoQ10) levels in patients with chronic heart failure.

Indications and regulation

Rosuvastatin is approved for the treatment of high LDL cholesterol (dyslipidemia
Dyslipidemia
Dyslipidemia or dyslipidaemia is an abnormal amount of lipids in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood, often due to diet and lifestyle. The prolonged elevation of insulin levels can lead to dyslipidemia...

), total cholesterol (hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...

), and/or triglycerides (hypertriglyceridemia
Hypertriglyceridemia
In medicine, hypertriglyceridemia denotes high blood levels of triglycerides, the most abundant fatty molecule in most organisms. It has been associated with atherosclerosis, even in the absence of hypercholesterolemia . It can also lead to pancreatitis in excessive concentrations In medicine,...

). In February 2010, rosuvastatin was approved by the FDA for the primary prevention of cardiovascular events.

As of 2004, rosuvastatin had been approved in 154 countries and launched in 56. Approval in the United States by the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 came on August 12, 2003.

The results of the JUPITER trial
JUPITER trial
The JUPITER trial is a study aimed at evaluating whether statins reduce heart attacks and strokes in people with normal cholesterol levels.- Study rationale :JUPITER was a randomized double-blind placebo-controlled study...

 (2008) suggested that rosuvastatin may decrease the relative risk
Relative risk
In statistics and mathematical epidemiology, relative risk is the risk of an event relative to exposure. Relative risk is a ratio of the probability of the event occurring in the exposed group versus a non-exposed group....

 of heart attack and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

 in patients without hyperlipidemia
Hyperlipidemia
Hyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia is the condition of abnormally elevated levels of any or all lipids and/or lipoproteins in the blood...

 but with elevated levels of highly-sensitive C-reactive protein. This could strongly impact medical practice by placing many patients on statin prophylaxis that otherwise would have been untreated. As a result of this clinical trial, the FDA approved rosuvastatin for the primary prevention of cardiovascular events.

The AURORA trial
AURORA trial
The AURORA trial was a randomized, double-blind, placebo-controlled study investigating the use of rosuvastatin in the prevention of cardiovascular disease among patients undergoing chronic hemodialysis.The trial was undertaken because although patients...

 randomized 2776 patients undergoing hemodialysis due to kidney damage to receive either rosuvastatin or placebo. The randomized, double-blind study (2005 to 2009) found no difference in the two groups in the primary end-point, a combination of cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke. The study found no difference in all-cause mortality among this population at a mean follow-up of 3.8 years.

Effects on cholesterol levels

The effects of rosuvastatin on LDL cholesterol are dose-related. At the 10 mg dose, the average LDL cholesterol reduction was found to be 46% in one trial. Increasing the dose from 10 mg to 40 mg gave a modest additional 9% absolute reduction in LDL levels (55% below baseline levels).

FDA advisory for Asian patients

According to the FDA, the risk of myopathy during rosuvastatin therapy may be increased in Asian-Americans:
Because Asians appear to process the drug differently, half the standard dose can have the same cholesterol-lowering benefit in those patients, though a full dose could increase the risk of side-effects, a study by the drug's manufacturer, AstraZeneca, indicated.


Therefore, physicians should start Asian patients at the lowest dose level.

Patent protection

The main patent protecting rosuvastatin (RE37,314 - due to expire in 2016) was challenged as being an improper reissue of an earlier patent. This challenge was rejected in 2010, confirming protection until 2016.

Marketing

The drug was billed as a super-statin during its clinical development; the claim was that it offers high potency and improved cholesterol reduction compared to rivals in the class. The main competitors to rosuvastatin are atorvastatin
Atorvastatin
Atorvastatin , sold by Pfizer under the trade name Lipitor, 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...

 (Lipitor) and simvastatin
Simvastatin
Simvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...

 (Zocor). However, people can also combine ezetimibe with either rosuvastatin or atorvastatin and other agents on their own, for somewhat similar augmented response rates. So far, some published information for comparing rosuvastatin, atorvastatin, and ezetimibe/simvastatin results is available, but many of the relevant studies are still in progress.

First launched in 2003, sales of rosuvastatin were $129 million and $908 million in 2003 and 2004, respectively, with a total patient treatment population of over 4 million by the end of 2004.
Typical per patient costs to the UK NHS are £18.03-26.02/month (compared to £0.85-1.37/month for simvastatin
Simvastatin
Simvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...

).

Debate & criticisms

In October 2003, several months after its introduction in Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...

, Richard Horton
Richard Horton
Richard Horton, FRCP FMedSci, is the present editor-in-chief of The Lancet, a United Kingdom-based medical journal.-Education and career:...

, the editor of the medical journal
Medical journal
A public health journal is a scientific journal devoted to the field of public health, including epidemiology, biostatistics, and health care . Public health journals, like most scientific journals, are peer-reviewed...

 The Lancet
The Lancet
The Lancet is a weekly peer-reviewed general medical journal. It is one of the world's best known, oldest, and most respected general medical journals...

, criticized the way Crestor had been introduced. "AstraZeneca's tactics in marketing its cholesterol-lowering drug, rosuvastatin, raise disturbing questions about how drugs enter clinical practice and what measures exist to protect patients from inadequately investigated medicines," according to his editorial. The Lancet's editorial position is that the data for Crestor’s superiority relies too much on extrapolation from the lipid profile data (surrogate endpoints) and too little on hard clinical endpoints, which are available for other statins that had been on the market longer. The manufacturer responded by stating that few drugs had been tested so successfully on so many patients. In correspondence published in The Lancet, AstraZeneca's CEO Sir Tom McKillop
Tom McKillop
Sir Thomas Fulton Wilson McKillop, born 19 March 1943, is a chemist, pharmaceutical company CEO and former chairman of RBS Group.McKillop was born in Dreghorn, a small village near the town of Irvine in Ayrshire, Scotland and educated at Irvine Royal Academy and then Glasgow University, where he...

 called the editorial "flawed and incorrect" and slammed the journal for making "such an outrageous critique of a serious, well-studied medicine."

In 2004, the consumer interest organization Public Citizen
Public Citizen
Public Citizen is a non-profit, consumer rights advocacy group based in Washington, D.C., United States, with a branch in Austin, Texas. Public Citizen was founded by Ralph Nader in 1971, headed for 26 years by Joan Claybrook, and is now headed by Robert Weissman.-Lobbying Efforts:Public Citizen...

 filed a Citizen's Petition with the FDA, asking that Crestor be withdrawn from the US market. On March 11, 2005, the FDA issued a letter to Sidney M. Wolfe, M.D. of Public Citizen both denying the petition and providing an extensive detailed analysis of findings that demonstrated no basis for concerns about rosuvastatin compared with the other statins approved for marketing in the United States.

Myopathy

As with all statins, there is a concern of rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...

, a severe undesired side-effect. The FDA has indicated that "it does not appear that the risk [of rhabdomyolysis] is greater with Crestor than with other marketed statins", but has mandated that a warning about this side-effect, as well as a kidney toxicity warning, be added to the product label.

External links

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