Drug Criteria & Outcomes
Cerivastatin (Baycol)for cholesterol
By Lorie E. Butner, PharmD
Medical University of South Carolina
Charleston
Indications:
Cerivastatin (Baycol), by Bayer Corp., is classified as an antilipemic agent and is indicated for treatment of elevated cholesterol in patients with primary hypercholesterolemia and mixed dyslipidemia after dietary cholesterol and saturated fat restrictions have failed.1,2
Pharmacology:
The coenzyme 3-hydroxy-3-methylglutaryl (HMG-CoA) reductase is responsible for conversion of HMG-CoA to mevalonate, a precursor of cholesterol. Cerivastatin is an inhibitor of the HMG-CoA reductase coenzyme. By preventing production of cholesterol in the liver, cerivastatin promotes synthesis of low-density lipoprotein (LDL) receptors. An increased production of LDL receptors results in enhanced uptake of LDL and, ultimately, reduced plasma levels of circulating LDL. LDLs have been identified as a major culprit in cardiovascular disease.2,3
Pharmacokinetics:
Absorption: The absolute bioavailability of cerivastatin is 60%. Linear pharmacokinetics are demonstrated with cerivastatin at doses between 0.05 mg to 0.4 mg per day. Mean time to maximum concentration approximates 2.5 hours. Admin-istration with food does not affect the rate or extent of absorption of cerivastatin.2
Distribution: Cerivastatin is greater than 99% bound to plasma proteins.4 The volume of distribution is approximately 0.3L/kg.2
Metabolism: The cytochrome p450 enzyme system plays a role in the metabolism of cerivastatin to its metabolites. The isoenzymes responsible for metabolism are 3A4, 2C8, and 2A6. Two active metabolites, M1 and M23, are formed from demethylation and hydroxylation of the parent compound. The parent compound is responsible for the majority of the lipid-lowering effects.2,4
Excretion: Undetectable amounts of cerivastatin are found in the urine and feces. Approximately 30% of the drug is excreted in the urine as metabolites. The elimination half-life of cerivastatin ranges between two and three hours.2
Renal Impairment: Patients with moderate to severe renal impairment (ClCr < 60mL/min) have shown up to a 23% increase in drug concentrations and a 47% increase in half-life than in healthy individuals (ClCr > 90 mL/min).2
Hemodialysis: Cerivastatin has not been studied in patients with end-stage renal disease. However, due to the high degree of protein binding, cerivastatin is not expected to be removed by hemodialysis.2
Selected clinical trials:
Hanefeld and colleagues5 evaluated the safety and efficacy of cerivastatin 0.3 mg and 0.4 mg vs. placebo in 349 patient with primary hypercholesterolemia. All cerivastatin and placebo doses were administered by mouth. Primary hypercholesterolemia was defined as an LDL cholesterol > 190 mg/dL, in association with at least one risk factor. Risk factors included male gender, current cigarette smoker, history of premature coronary heart disease in the family, hypertension, HDL cholesterol concentrations < 35 mg/dL, history of cerebrovascular or peripheral vascular disease, coronary disease, and obesity. Patients 18 to 75 years of age who were ambulatory with a triglyceride level > 350 mg/dL were included in the study. Patients were excluded from the study if they had a contraindication to statin therapy, severe hypertension, myocardial infarction within the past six months, congestive heart failure (New York Heart Association class III or IV), or cardiac arrhythmias.
Other exclusion criteria included a history of cerebrovascular event, malignancy, endocrine disorders (e.g., diabetes mellitus and hypothyroidism), pancreatitis, muscular or neuromuscular disease, or impaired gastric absorption. Females of childbearing potential were excluded from participation, as were night shift workers and patients on concomitant lipid-lowering therapies. Patients taking immunosuppressive agents, erythromycin, niacin, or any form of corticosteroids were excluded from participation in the study. In addition, patients with elevated creatine kinase (CK) levels (greater than three times the upper normal limit) or liver function tests (LFTs) (greater than one and one-half times the upper normal limit) were excluded.5
A total of 349 patients were treated with cerivastatin 0.3 mg (n = 140), cerivastatin 0.4 mg (n = 138), or placebo (n = 71) once daily for eight weeks. All patients received American Heart Association Step-1 dietary counseling. Prior to initiating therapy, patients participated in an optional four-week dietary stabilization phase based on investigators’ recommendation. A six-week placebo run-in phase prior to randomization allowed patient assessment to dietary adherence and medication compliance. Baseline cholesterol parameters were also evaluated during this phase of the study. Adverse drug reactions were documented at each visit. Patients were withdrawn from the study if CK levels reached 10 times the upper normal limit, if CK levels were greater than five times normal on two occasions, or if CK levels were greater than three times normal accompanied by muscle weakness or pain. In addition, LFTs greater than three times the upper normal limit or an LDL cholesterol level less than 60 mg/dL were reasons for study discontinuation.5
The primary endpoint measured was change from baseline in LDL cholesterol concentrations. Baseline values were calculated as the mean LDL from patient visits 3, 4, and 5. Low-density lipoprotein concentrations were calculated using the Friedewald Formula. The data were analyzed using an intent-to-treat analysis. Patients were included in the final analysis if they had one LDL cholesterol concentration from visits 3, 4, or 5 and one level during the treatment period. Secondary endpoints were change in baseline of total cholesterol, HDL cholesterol, triglyceride, and certain lipid fractions.5
The group treated with cerivastatin 0.4 mg had a mean decrease in LDL cholesterol concentrations of 35.8%, whereas those treated with cerivastatin 0.3 mg had a mean decrease in LDL cholesterol concentrations of 32.5%. Statistical significance was not found between cerivastatin-treated patients. Patients receiving placebo experienced a mean increase of 0.2% in LDL cholesterol concentrations. Statistical significance was achieved for both cerivastatin groups compared to placebo (p < 0.001). In the cerivastatin 0.3 mg and cerivastatin 0.4 mg groups, 27.9% and 40.6% of patients, respectively, experienced a drop in LDL cholesterol concentrations greater than 40%. Total cholesterol concentrations in the cerivastatin 0.4 mg treatment group decreased significantly from baseline compared to cerivastatin 0.3 mg and placebo (26.8% and 24.3% for 0.4 mg and cerivastatin 0.3 mg; p < 0.02).
Other lipid parameters including triglycerides and apolipoprotein levels decreased significantly in both treatment groups as compared to placebo. No patients withdrew from the study secondary to an adverse event related to the study medication. Back pain and headache were the only two adverse events that had a higher incidence among patients on cerivastatin than those on placebo. Back pain was reported in 1.4% of placebo patients vs. 2.9% and 4.3% of patients on 0.3 mg and cerivastatin 0.4 mg, respectively. Headache occurred in 1.4% of placebo-treated patients, 2.1% of patients on cerivastatin 0.3 mg, and 4.3% of patients assigned to cerivastatin 0.4 mg daily.5
The data support that cerivastatin 0.4 mg daily was associated with a greater reduction in LDL and total cholesterol concentrations than previously studied doses in patients with primary hyperlipidemia. No increase in adverse events was noted at the higher dosage.5
A study by Stein and colleagues6 demonstrated the safety and efficacy of cerivastatin 0.8 mg. Forty-one patients were assigned to receive either cerivastatin 0.8 mg (n = 28) or placebo (n = 13) by mouth daily for 28 days in this randomized, double-blind, parallel group trial. Patients with primary hypercholesterolemia were evaluated. Patients with recent acute cardiovascular events or interventions; uncontrolled hypertension, diabetes mellitus or other endocrine abnormalities; unstable ophthalmic problems; malignancy; active liver disease; gastrointestinal disorders with potential to impair absorption; pregnant or lactating females; and patients currently taking aspirin, corticosteroids, rifampin, immunosuppressants, antidiabetic medications, or other lipid-lowering agents were excluded.6
Cerivastatin 0.8 mg lowered LDL cholesterol by 44% over a 28-day period, whereas placebo-treated patients experienced a 1.2% increase in LDL cholesterol concentrations (p lt; 0.0001). Total cholesterol and triglyceride concentrations were also reduced by 30.8% and 11.2%, respectively, in the cerivastatin-treated group (Table 1). High-density lipoprotein (HDL) was raised 3.2% from baseline in the cerivastatin-treated group, while a decrease of 1.2% was noted in placebo-treated patients. Eighteen of 28 patients (64%) in the cerivastatin-treated group experienced one adverse event and seven of 13 patients (54%) in the control arm reported an adverse event. Events were classified as mild or moderate. Reported events occurred at the following rates in cerivastatin- and placebo-treated patients, respectively: headache (n = 10, 36%; n = 2, 15%), pharyngitis (n = 3, 11%; n = 0, 0%), back pain (n = 2, 7%; n = 1, 8%), arthralgia (n = 2, 7%; n = 1, 8%), and rash (n = 2, 7%; n = 0, 0%). No adverse effects resulted in discontinuation of medication.6
Adverse reactions:
More than 4,000 patients have been evaluated in clinical trials. Cerivastatin was generally well-tolerated. Adverse reactions occurring in greater than 5% of 1,263 patients treated with cerivastatin include headache (n = 124; 9.8%), pharyngitis (n = 160; 12.7%), sinusitis (n = 80; 6.3%), rhinitis (n = 136; 10.8%), and accidental injury (n = 64; 5.1%). These reactions were similar to those experienced by placebo-treated patients. Other adverse events included arthralgias (n = 55; 4.4%) and myalgias (n = 29; 2.3%), back pain (n = 50; 4%), and dyspepsia (n = 53; 4.2%).2
Increases in LFTs have been observed with cerivastatin. Patients should have baseline LFTs measured prior to initiating therapy and again at six and 12 weeks. Thereafter, LFTs should be evaluated periodically. Most liver toxicity occurs by week six of therapy. If LFTs increase greater than three times normal, then cerivastatin should be discontinued.2
Myopathy accompanied by an increase in CK has been observed rarely with cerivastatin. Increased risk of myopathy occurs if cerivastatin is given in combination with cyclosporine, erythromycin, antifungal agents with azole structures, fibric acid agents, and niacin.2
Pregnancy and lactation:
Cerivastatin is pregnancy category X. The drug caused incomplete bone formation in the vertebrae of rats at oral doses of 0.72 mg/kg. Drug concentrations in plasma were six to seven times higher than the human exposure for rats. In pregnant rats given cerivastatin 2 mg/kg, the drug was found in fetal liver, gastrointestinal tract, and kidneys. No growth abnormalities were observed in rabbits receiving doses as high as 0.75 mg/kg. Safety of cerivastatin in pregnant human patients has not been established; however, rare cases of fetal abnormalities have been reported with other HMG-CoA reductase inhibitors used during pregnancy. If a patient becomes pregnant while on cerivastatin, the medication should be discontinued immediately.2
Contraindications:
Patients with active liver disease or an unexplained increase in transaminase levels should avoid treatment with cerivastatin. Cerivastatin is contraindicated in pregnant and lactating females. Females of childbearing potential should also avoid cerivastatin therapy. Cerivastatin is contraindicated in patients with hypersensitivity to any component of the medication.2
Warnings:
Patients with a history of liver disease or alcoholism should be closely monitored while on cerivastatin therapy. Cerivastatin treatment should be temporarily discontinued in patients with circumstances predisposing them to renal failure from rhabdomyolysis.2
Dosage and administration:
In addition to a standard cholesterol-lowering diet, patients who have failed diet therapy alone should start drug therapy with cerivastatin 0.4 mg in the evening. Patients with creatinine clearance < 60 mL/min should start therapy with lower doses (cerivastatin 0.2 mg or 0.3 mg).2
Monitoring parameters:
Cholesterol levels should be rechecked approximately four weeks after initiating therapy. Recommendations for obtaining LFTs include baseline values, at weeks six and 12 of therapy, and periodically thereafter.2
Drug interactions:
No clinically significant pharmacokinetic changes have been detected when either warfarin, digoxin, cimetidine, antacids, or omeprazole was given in combination with cerivastatin. Cholestyramine coadministration has shown a decrease in AUC and concentration of cerivastatin. Gemfibrozil coadministration may cause an increased risk of rhabdomyolysis and renal failure. Erythromycin and itraconazole have also been shown to impact cerivastatin concentrations; coadministration may result in increased cerivastatin concentrations and increased half-life. The clinical significance of these interactions is unknown. Cerivastatin is metabolized by both renal and hepatic pathways and may, therefore, be associated with fewer drug interactions than other HMG-CoA reductase inhibitors.2
Dosage forms available:
Tablets for oral administration are available in 0.2 mg (light yellow), 0.3 mg (yellow brown), and 0.4 mg (ocher) strengths.2
Discussion:
Cardiovascular disease is responsible for more than 900,000 deaths in the United States each year.7 In addition to smoking and hypertension, hyperlipidemia is one of the most dangerous risk factors for developing coronary artery disease (CAD).7 In the late 1980s, the Multiple Risk Factor Intervention Trial (MRFIT) showed the association between increased cholesterol levels and coronary artery disease.8 Decreasing LDL levels may prevent further decline in cardiovascular risk and may even clear the arteries of some pre-existing disease.7 The National Cholesterol Education Program guidelines recommend decreasing LDL cholesterol to less than 100 mg/dL in patients with coronary heart disease.3
Several drugs have been developed to inhibit this rate-limiting step in cholesterol synthesis. Cerivastatin is the newest agent in this class to be approved by the FDA. Although cerivastatin specifically has not been evaluated in clinical trials for CAD, data from trials using pravastatin and simvastatin have demonstrated a decrease in morbidity and mortality in patients with primary and secondary CAD. As with other statins recently approved by the FDA, cerivastatin may demonstrate a class effect in the reduction of CAD and death associated with hypercholesterolemia. Due to this class effect, cerivastatin may prove to be a valuable medication for cholesterol treatment. In the future, more aggressive dosing regimens may bring an additional increase in LDL lowering.6
To date, drug interactions with cerivastatin are minimal. Compared to other HMG-CoA reductase inhibitors, cerivastatin has no significant drug interactions with warfarin or digoxin, an important consideration in a large population of patients being either prophylaxed or treated for CAD.
References:
1. McEvoy GK, ed. AHFS Drug Information. Bethesda: American Society of Health-System Pharmacists, Inc.; 1999.
2. Baycol package insert. West Haven, CT: Bayer Corp.; 1999 May.
3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). JAMA 1993;269(23):3015-3023.
4. McClellan KJ, Wiseman LR, McTavish D. Cerivastatin. Drugs 1998;55(3):415-22.
5. Hanefeld M, Deslypere J-P, Ose L, et al. Efficacy and safety of .3 mg and .4 mg cerivastatin once daily in patients with primary hypercholesterolemia: a multicenter, randomized, double-blind, placebo-controlled study. J Intern Med Res 1999;27:115-29.
6. Stein E, Isaacsohn J, Stoltz R, et al. Efficacy and safety of 0.8 mg dosage of cerivastatin, a novel HMG-CoA reductase inhibitor. J Am Coll Cardiol 1998:281A.
7. Farnier M, Davignon J. Current and future treatment of hyperlipidemia: the role of statins. Am J Cardiol 1998;82:3J-10J.
8. Martin MJ, Browner WS, Hulley SB, et al. Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361 662 men. Lancet 1986:933-6.
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