A case for lower dose of rosuvastatin

Unless ongoing trial results lead to a different conclusion, the use of 40mg and 20mg should be as restricted in Asian patients as it may be bioequivalent to a dose of 80mg and 40mg in Caucasians, says Dr Krishan Maggon

Although the pre-approval clinical trial programme for rosuvastatin involved more than 10,000 patients, by 2004 more than 42,000 patients were treated with rosuvastatin in clinical trials. The safety and tolerability of rosuvastatin have been assessed (as of August 2003) using data from 12,400 patients who received five to 40 mg of rosuvastatin in the phase II/III clinical development programme and are summarised in recent reviews.

Last year, the author in a series of articles in this paper, had made a case for the use of lower one mg, 2.5mg, 5mg and 10mg rosuvastatin dose in India. I am not sure that if any Indian company introduced lower dosage formulations in 2004.

The recent approval of rosuvastatin in Japan at 2.5mg as the starting dose and 5, 10 and 20mg dose coupled with AstraZeneca ongoing trials at lower doses add some credibility to such recommendations. FDA recommended that for Asians patients living in USA, the starting dose should be 5mg with a maximum of 20mg.

The AUC and Cmax of rosuvastatin were doubled in 18 Japanese healthy subjects and Chinese living in Singapore. The bioavailability of the drug was increased from 20 per cent in Caucasians to 29 per cent in Japanese subjects. In a pilot clinical trial in Japan, 1, 2.5, 5, 10, 20 and 40 mg daily dose were used in 112 patients for six weeks. Mean reductions in LDL-C were 35.8 per cent to 66 per cent, were linear and each doubling of dose produced additional 5.12 per cent reduction.

Unless ongoing trial results lead to a different conclusion, the use of 40mg and 20mg should be as restricted in Asian patients as it may be bioequivalent to a dose of 80mg and 40mg in Caucasians. FDA medical reviewer recommended approval of the one and 2.5mg doses but Astra Zeneca did not develop or market the low doses. It is the only statin to show increased risk of higher toxicity for Asians at doses used in the West.

With the obesity epidemic in USA and Europe, the lower body weight of the Asian populations point to use of lower doses. Based on the review of safety and efficacy data submitted to the FDA, for Asian patients, doses much lower then 5mg may be clinically adequate.

The one mg, 2.5mg and 5mg doses provided 60, 73 and 87 per cent of the clinical benefits of the 20mg dose in Caucasian patients. The one mg dose provided half of the benefit of 40 mg dose in Japanese patients, in Indian patients similar increased efficacy is expected. Thus the starting safe and effective dose for Asian patients can be anywhere from one to five mg (tables 1, 2).

All other marketed statins carry a risk of rhabdomyolysis and kidney failure, which is dose related. The UK Committee on Safety of Medicines (CSM) which monitors drug safety reports about one case report of rhabdomyolysis for every 100,000 patients, for each year of treatment with any statin. The CSM analysis suggested that the 40mg dose benefits a small percentage of patients; it may be associated with a higher rate of side effects, including rhabdomyolysis.

An FDA review of reports of rhabdomyolysis in other currently marketed statins found that the rate of reports per million US prescriptions ranged from none for fluvastatin to 1.2 per million for lovastatin, the next highest being 0.8 for simvastatin, then 0.3 for atorvastatin. Cerivastatin, now banned, was highest at 18.1 per million.

The package insert in Europe has been modified to limit the use of 40mg dose of rosuvastatin as starting dose, which was used, by small number (5 per cent) of the patients with previously uncontrollable lipid disorders and with predisposing factors for myopathy and rhabdomyolysis.

FDA advises healthcare professionals prescribing rosuvastatin that start doses and maintenance doses of drug should be based on individual cholesterol goals and apparent risks for side-effects; all patients should be informed that statins can cause muscle injury, which in rare and severe cases, can cause kidney damage and other organ failure that are potentially life-threatening; and patients should be told to promptly report to their physician signs or symptoms of muscle pain and weakness, malaise, fever, dark urine, nausea, or vomiting.

The low dose 10 mg of simvastatin was approved for OTC use in the UK for individuals who are at moderate risk for heart disease. These would include all men 55 or older, and men 45-55 and women over 55 who have at least one risk factor. In a double-blind placebo controlled study in 210 subjects, low dose lovastatin was effective in 75 per cent of the subjects in achieving their LDL-cholesterol goal of 130 mg/dl.

Data from clinical trials of low dose pravastatin 10mg and lovastatin 10mg was submitted to FDA but the application for OTC status was rejected in 2004 because of insufficient evidence that either drug could be used safely and effectively. Thus starting statin dose should be based on the reduction in LDL-C (the bad, low density lipoprotein-cholesterol) tailored to individual patient.

Many patients do need high dose potent statins. The lowest marketed dose of atorvastatin 10 mg reduces LDL-C 39 per cent, a strong response needed by cardiac patients and people with severely elevated cholesterol, rosuvastatin dose is only 2.5 mg for similar reduction. Most people with high cholesterol have mild-to-moderate elevations and no cardiac history, and they require only 20 per cent to 30 per cent reductions in LDL-C. This can be attained with only 2.5mg or five mg of atorvastatin or one mg to 2.5mg of rosuvastatin.

Simvastatin standard starting dose 20 mg, reduces LDL-C by 38 per cent. Many people need only 10mg or even 5 mg, which reduce LDL-C 30 per cent and 26 per cent, respectively. The recent trials of low dose statins for OTC use in some European countries have established the efficacy and safety.

Table 2. Efficacy of Lower doses of rosuvastatin
Dose	Rosuvastatin	Atorvastatin	Simvastatin
mg	% Reduction in LDL_C
1	33	-	-
2.5	38	22	-
5	45	28	26
10	52	39	30
20	55	43	-
40	62	50	-
80	-	60	-

The writer is Geneva-based pharma biotech R&D advisor.
E-mail: maggonk@yahoo.com