Drugs

, Volume 60, Issue 5, pp 1179–1206 | Cite as

Cerivastatin

A Review of its Pharmacological Properties and Therapeutic Efficacy in the Management of Hypercholesterolaemia
  • Greg L. Plosker
  • Christopher J. Dunn
  • David P. Figgitt
Adis Drug Evaluation

Summary

Abstract

Cerivastatin is an HMG-CoA reductase inhibitor used for the treatment of patients with hypercholesterolaemia. The lipid-lowering efficacy of cerivastatin has been demonstrated in a number of large multicentre, randomised clinical trials. Earlier studies used cerivastatin at relatively low dosages of ≤0.3mg orally once daily, but more recent studies have focused on dosages of 0.4 or 0.8 mg/day currently recommended by the US Food and Drug Administration (FDA).

Along with modest improvements in serum levels of triglycerides and high density lipoprotein (HDL)-cholesterol, cerivastatin 0.4 to 0.8 mg/day achieved marked reductions in serum levels of low density lipoprotein (LDL)-cholesterol (33.4 to 44.0%) and total cholesterol (23.0 to 30.8%). These ranges included results of a pivotal North American trial in almost 1000 patients with hypercholesterolaemia. In this 8-week study, US National Cholesterol Education Program (Adult Treatment Panel II) [NCEP] target levels for LDL-cholesterol were achieved in 84% of patients randomised to receive cerivastatin 0.8 mg/day, 73% of those treated with cerivastatin 0.4 mg/day and <10% of placebo recipients. Among patients with baseline serum LDL-cholesterol levels meeting NCEP guidelines for starting pharmacotherapy, 75% achieved target LDL-cholesterol levels with cerivastatin 0.8 mg/day. In 90% of all patients receiving cerivastatin 0.8 mg/day, LDL-cholesterol levels were reduced by 23.9 to 58.4% (6th to 95th percentile). Various subanalyses of clinical trials with cerivastatin indicate that the greatest lipid-lowering response can be expected in women and elderly patients.

Cerivastatin is generally well tolerated and adverse events have usually been mild and transient. The overall incidence and nature of adverse events reported with cerivastatin in clinical trials was similar to that of placebo. The most frequent adverse events associated with cerivastatin were headache, GI disturbances, asthenia, pharyngitis and rhinitis. In the large pivotal trial, significant elevations in serum levels of creatine kinase and transaminases were reported in a small proportion of patients receiving cerivastatin but not in placebo recipients. As with other HMG-CoA reductase inhibitors, rare reports of myopathy and rhabdomyolysis have occurred with cerivastatin, although gemfibrozil or cyclosporin were administered concomitantly in most cases.

Postmarketing surveillance studies in the US have been performed. In 3 mandated formulary switch conversion studies, cerivastatin was either equivalent or superior to other HMG-CoA reductase inhibitors, including atorvastatin, in reducing serum LDL-cholesterol levels or achieving NCEP target levels. Pharmacoeconomic data with cerivastatin are limited, but analyses conducted to date in the US and Italy suggest that cerivastatin compares favourably with other available HMG-CoA reductase inhibitors in terms of its cost per life-year gained.

Conclusion: Cerivastatin is a well tolerated and effective lipid-lowering agent for patients with hypercholesterolaemia. When given at dosages currently recommended by the FDA in the US, cerivastatin achieves marked reductions in serum levels of LDL-cholesterol, reaching NCEP target levels in the vast majority of patients. Thus, cerivastatin provides a useful (and potentially cost effective) alternative to other currently available HMG-CoA reductase inhibitors as a first-line agent for hypercholesterolaemia.

Pharmacodynamic Properties

Animal and in vitro data have shown that cerivastatin has a high affinity for HMG-CoA reductase and that it inhibits hepatic cholesterol synthesis at concentrations around 100 times lower than those of lovastatin. The demethylated (M1) and hydroxylated (M23) metabolites of cerivastatin have inhibitory activity similar to that of the parent compound. Studies in animals and healthy volunteers showed that serum lipid responses to cerivastatin are dose dependent. Mean serum total and low density lipoprotein (LDL)-cholesterol levels were reduced relative to baseline by up to 26.3 and 36.4%, respectively, after 7 days’ treatment with cerivastatin 0.1 to 0.4 mg/day in a study in healthy volunteers.

Cerivastatin has shown vascular effects of interest in preclinical studies, most notably attenuation of proliferation of vascular smooth muscle cells, fibroblasts, endothelial cells and myoblasts. In one study, cerivastatin was shown to possess greater potency in terms of drug concentrations required to inhibit cell proliferation than all other commercially available HMG-CoA reductase inhibitors. Anti-atherogenic effects such as inhibition of monocyte adhesion to vascular endothelium, and stabilisation of fibrous material in stenotic plaques, have also been reported. Cerivastatin has also been associated with improved endothelial function, shown by markedly and statistically significant increases relative to placebo in forearm blood flow in patients receiving 0.4 mg/day for 2 weeks. The drug has no apparent effect on insulin sensitivity, but has been associated with suppression of serum evels of steroid sex hormones in women.

Pharmacokinetic Properties

Cerivastatin undergoes near-complete GI absorption after oral administration (with no clinically relevant interference by food), but undergoes first-pass metabolism and has an absolute bioavailability of 60%. Maximum plasma concentrations are attained after 2 to 3 hours. The drug exhibits linear pharmacokinetics over the dose range 0.15 to 0.8mg. Cerivastatin is highly bound to plasma proteins (>99%) and has a volume of distribution of approximately 0.3 L/kg.

Metabolism is via hepatic cytochrome P450 (CYP) 3A4 and 2C8 to yield demethylated (M1) and hydroxylated (M23) active major metabolites. These metabolites contribute ≈20 to 25% of the total activity of each dose of cerivastatin. Approximately 70% of a dose is excreted in the faeces, with intact cerivastatin accounting for less than 2% of the total originally administered. The plasma elimination half-life after oral administration is 2 to 3 hours. The pharmacokinetic characteristics of cerivastatin are not affected by advanced age, gender or ethnicity.

Patients with moderate to severe renal impairment have shown an increase in 24-hour area under plasma cerivastatin concentration versus time curve of up to approximately 60% relative to healthy individuals. Mild renal impairment (creatinine clearance 3.7 to 5.4 L/h per 1.73m2) does not have any clinically relevant effect on the pharmacokinetics of the drug.

As a result of dual hepatic metabolism of cerivastatin, no potentially significant drug interactions with cerivastatin have been noted with the CYP3A4 inhibitors erythromycin and itraconazole. However, the bile acid sequestrant cholestyramine has been shown to impair the absorption of cerivastatin, and a temporal separation of the administration of these 2 drugs has been recommended. Coadministration of the immunosuppressant cyclosporin and cerivastatin resulted in increased plasma concentrations of the latter in a study in 12 renal transplant recipients. There were no effects on the elimination of cerivastatin or on steady-state plasma concentrations of cyclosporin or its metabolites, however.

Therapeutic Efficacy

The lipid-lowering efficacy of cerivastatin has been demonstrated in a number of large multicentre, randomised studies in patients with hypercholesterolaemia. Earlier studies evaluated cerivastatin at dosages of 0.1 to 0.3 mg/day for 4 to 32 weeks. These studies reported dose-related reductions from baseline in serum levels of total cholesterol ranging from 12.9 to 24.4%, and in LDL-cholesterol ranging from 15.1 to 33.6%. High density lipoprotein (HDL)-cholesterol levels increased by 2.3 to 11.4% with cerivastatin 0.1 to 0.3 mg/day. In general, a treatment response was observed after 1 week of therapy and was maximal by about 3 or 4 weeks.

More recent studies have focused on the lipid-lowering efficacy of cerivastatin at dosages of 0.4 to 0.8 mg/day in patients with hypercholesterolaemia. Cerivastatin 0.4 to 0.8 mg/day was associated with improvements from baseline in serum levels of total cholesterol (−23.0 to −30.8%), LDL-cholesterol (−33.4 to −44.0%), HDL-cholesterol (+3.2 to +8.7%) and triglycerides (−10.4 to −18.4%). These ranges include results of a pivotal multicentre study in almost 1000 patients with primary hypercholesterolaemia. In this 8-week trial, 84% of patients randomised to receive cerivastatin 0.8 mg/day achieved US National Cholesterol Education Program (Adult Treatment Panel II) [NCEP] target levels for LDL-cholesterol compared with 73% of those treated with cerivastatin 0.4 mg/day and <10% of placebo recipients. Among patients with baseline serum LDL-cholesterol levels meeting NCEP guidelines for pharmacotherapy, 75% achieved target LDL-cholesterol levels with cerivastatin 0.8 mg/day. Overall, in 90% of patients receiving cerivastatin 0.8 mg/day, LDL-cholesterol levels were reduced by 23.9 to 58.4% (6th to 95th percentile). One-year follow-up data from this trial showed that the lipid-lowering efficacy of cerivastatin was maintained on a long term basis.

Postmarketing surveillance studies in the US have been performed. In 3 mandated formulary switch conversions, cerivastatin was either equivalent or superior to other HMG-CoA reductase inhibitors, including atorvastatin, in reducing serum LDL-cholesterol levels or achieving NCEP target levels.

Various subanalyses of clinical trials with cerivastatin indicate both age- and gender-related effects. Thus, cerivastatin effectively lowers serum levels of LDL-cholesterol to a greater extent in women than men and in elderly than younger patients.

Tolerability

In general, cerivastatin has been well tolerated in clinical trials, and adverse events have usually been mild and transient. The most frequently reported adverse events with cerivastatin were headache, GI disturbances, asthenia, pharyngitis and rhinitis, although there were essentially no clinically important differences between the overall tolerability profile of cerivastatin and that of placebo. In 2 large pooled analyses, adverse events were reported in approximately 60 to 65% of patients receiving cerivastatin up to 0.4 mg/day or placebo. Discontinuation of therapy because of adverse events occurred in 2.8 and 3.0% of cerivastatin (up to 0.4 mg/day) recipients compared with 2.2 and 2.5% of placebo recipients in the 2 analyses. Adverse events associated with cerivastatin did not appear to be dose related according to pooled results from studies with cerivastatin 0.1 to 0.4 mg/day and data from a pivotal placebo-controlled trial comparing cerivastatin 0.4 and 0.8 mg/day. A small proportion of patients receiving cerivastatin in the pivotal trial had significant elevations in serum levels of creatine kinase and transaminases, whereas these laboratory abnormalities were not reported among placebo recipients.

As with other HMG-CoA reductase inhibitors, postmarketing surveillance data and published case reports indicate that rhabdomyolysis and associated renal failure have been reported (albeit rarely) with cerivastatin, and most cases involved concomitant administration of gemfibrozil or cyclosporin.

Dosage and Administration

The US Food and Drug Administration (FDA) recommends a starting dosage of cerivastatin 0.4mg orally once daily in the evening. The drug may be taken with or without food. If the response to therapy (including continuation of a standard cholesterol lowering diet) is inadequate, cerivastatin dosage may be increased to 0.8 mg/day. Lower dosages are recommended for patients with significant renal impairment. Contraindications to cerivastatin include pregnancy and lactation. The efficacy and tolerability of cerivastatin in paediatric patients have not been established.

Keywords

Simvastatin Atorvastatin Pravastatin Lovastatin Fluvastatin 

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Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • Greg L. Plosker
    • 1
  • Christopher J. Dunn
    • 1
  • David P. Figgitt
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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