Article: Rosuvastatin

Rosuvastatin
Systematic (IUPAC) name
7-[4-(4-fluorophenyl) -6-(1-methylethyl)- 2-(methyl-methylsulfonyl-amino)- pyrimidin- 5-yl]- 3,5-dihydroxy-hept-6-enoic acid
Identifiers
CAS number	287714-41-4
ATC code	C10AA07
PubChem	6439133
DrugBank	APRD00546
Chemical data
Formula	C22H28N3FO6S
Mol. weight	481.539
Pharmacokinetic data
Bioavailability	20%
Metabolism	Liver
Half life	19 hours
Excretion	Urine / Faeces
Therapeutic considerations
Pregnancy cat.	D(AU) X(US)
Legal status	S4(AU) POM(UK) ℞-only(US)
Routes	oral

Rosuvastatin is a member of the drug class of statins, used to treat hypercholesterolemia and related conditions, and to prevent cardiovascular disease. It is currently being marketed by the pharmaceutical company AstraZeneca as Crestor®.

Presentation

Rosuvastatin is available as Crestor in tablet form (5, 10, 20, or 40 mg) for oral administration. Tablets are pink, round or oval (40 mg), biconvex, film-coated, and imprinted with "ZD4522" and tablet strength.^[1] Japanese approval is in the dose range of 2.5 mg to 20 mg; therefore, smaller dose tablet forms might also be available outside the United States. Note that 97% of worldwide sales have been at or below the 20 mg dose.

Mechanism of action

See the article on statins for more details.

Rosuvastatin is a competitive inhibitor of the enzyme HMG-CoA reductase, having a mechanism of action similar, yet higher efficacy, to other statins, see the Nissen reference below.

Indications and regulation

Rosuvastatin is approved for the treatment of elevated LDL cholesterol (dyslipidemia), total cholesterol (hypercholesterolemia) and/or triglycerides (hypertriglyceridemia).^[2]

As of 2004, rosuvastatin had been approved in 67 countries and launched in 56. Approval in the United States by the FDA came on August 12, 2003.^[3]

Marketing and competition

Marketing

The drug was billed as a super-statin during its clinical development, claimed to offer a high potency and improved cholesterol reduction compared to rivals in the class. The main competitors to rosuvastatin are atorvastatin and the combination product ezetimibe/simvastatin (marketed as Vytorin by Merck & Co.). 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, see the Nissen refeneece below.

First launched in 2003, sales were $129 million and $908 million in 2003 and 2004, respectively, with a total patient treatment population of >4 million by the end of 2004.

Debate & Criticisms

Several months after its introduction in Europe, Richard Horton, the editor of the medical journal The Lancet, criticised 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 and too little on hard clinical endpoints, which are available for other statins which had been on the market longer. The manufacturer responded by claiming that few drugs had been tested so successfully on so many patients. In correspondence published in The Lancet, AstraZeneca's CEO Sir Tom McKillop called the editorial "flawed and incorrect" and slammed the journal for making "such an outrageous critique of a serious, well-studied medicine."^[4]

In 2004, the consumer interest organisation Public Citizen filed a Citizen's Petition with the FDA asking that Crestor be withdrawn from the US market. In 2005, the FDA, after a 14 month review of the specifics for each of the 35 individuals cited in the petition, formally denied this petition as not demonstrating any basis for additional concerns about rosuvastatin. Thirty two of the individuals had taken rosuvastatin at some time but the evidence was that their problems were most strongly related to other existing health issues and 3 of the 35 individuals had never taken rosuvastatin.

Myopathy

As with all statins, some doctors have been hesitant to prescribe rosuvastatin because of concerns that this agent might have a higher incidence of rhabdomyolysis (a severe undesired side effect) than other statins; this negative impact on sales performance has been much more pronounced in the United States than in other countries. 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.^[5] However, more recent, larger and more thorough reviews have actually demonstrated both slightly lower rates of myopathy for rosuvatatin than any of the other statins available within the United States and improved kidney function with all statin use, including rosuvastatin, see below.

Regarding myopathy and potential rhabdomyolysis, recent reviews of published data on all statins marketed in the US, and reviewed by the FDA, both pre and post-approval, have found that marked rises in the serum levels of muscle CK enzymes to 10 times normal or greater, the hallmark of serious muscle problems, remain very rare, 1:10,000 to 1:20,000 individuals. (For comparison, this incidence is about identical with that for acetominophen, commonly purchased as Tylenol, an OTC agent about which most people rarely worry; accept as safe)

Cerivastatin was an exception; it had a higher myopathy response. For the statins still on the market in the US, reported toxicity levels has been highest for pravastatin, simvastatin next, atorvastatin next and rosuvastatin the lowest at similar milligram doses. Yet the efficacy of these agents to change blood LDLipoproteins levels, at the same milligram doses, is the exact opposite. So, from the standpoint of the rare but serious muscle toxicity events, rosuvastatin, as of mid-2005 has turned out to have the best therapeutic index of the currently available statins.

Renal Effects

Recent reviews of published trial data, focusing on renal function, on placebo vs. statin, and tracking renal function over time have shown a small but distinct effect of statins to lessen renal dysfunction, when added to treatment (compared to placebo), and to slow the progression of further renal function decline over time. All the statins have a somewhat dose related response to increase urine protein levels, rosuvastatin the strongest association. Because increased urine protein has long been relied upon as a warning sign of renal glomerular dysfunction, this increase as a reault of statin treatment had been feared to indicate a negative effect on renal function.

However, all current evidence is that the increase in urinary protein is from the renal tubular cells, not the glomeruli, and is due to cholesterol synthesis inhibition within the tubular cells and is not associated with any decline in renal function. Instead, as mentioned above, clinical experience is that renal function, especially in those with partial renal failure, actually improves slightly and the rate of further decline decreases compared with those in the same trials who were randomized to the placebo agent.

Comments, Changing Evidence & Beliefs

In general, experience with human responses to the statin agents has increasingly and dramatically driven a shift of conclusions toward the concept that much of common adult cholesterol production and blood transport behavior is unhealthy, even though cholesterol is an essential component of all human cell membranes. Though it is normal (i.e. common) for blood concentrations of LDLipoproteins to progressively rise with age as people get older, this is also strongly associated with development and progression of atherosclerotic plaque, typically not present in children under age 5 when cholesterol content of the blood LDLipoproteins is typically about 35 mg/dl.

Scientists, physicians and the public continue to debate the issues and their varied and strongly held beliefs, yet clinical experience and research tracking of the benefits vs. risks has increasingly demonstrated realities contrary to the understanding and beliefs of many.

Human Trial Evidence and Better Information

More recent human controlled research trial data continues to be more promising. One of the most recent is a 2 year trial of rosuvastatin treatment, the ASTEROID trial, in which several hundred people were treated with Crestor 40 mg/day and IVUS was used to check results. Rosuvastatin, used at the highest currently approved dose, showed reversal of atherosclerotic plaque within the coronary arteries, the first statin to demonstrate this good, and long-hoped-for, outcome. See the Nissen et al. reference, "Effect of Very High-Intensity Statin Therapy on Regression of Coronary Atherosclerosis" below.