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These complexes can be separated via ultracentrifugation into high-density lipoprotein (HDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) fractions. In the liver, cholesterol and triglycerides (TG) are synthesized, incorporated into VLDL, and released into the plasma for delivery to peripheral tissues.
A variety of clinical studies have demonstrated that elevated levels of total cholesterol (total-C), LDL-C, and apolipoprotein B (apo-B, a membrane complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apolipoprotein A) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with nonlipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
In patients with hypercholesterolemia, BAYCOL® (cerivastatin (removed from market 8/2001)) (cerivastatin sodium tablets) has been shown to reduce plasma total cholesterol, LDL-C, and apolipoprotein B. In addition, it also reduces VLDL-C and plasma triglycerides and increases plasma HDL-C and apolipoprotein A-1. The agent has no consistent effect on plasma Lp(a). The effect of BAYCOL® (cerivastatin (removed from market 8/2001)) on cardiovascular morbidity and mortality has not been determined.
Mechanism of Action: Cerivastatin is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis by cerivastatin reduces the level of cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors, thereby increasing the uptake of cellular LDL particles. The end result of these biochemical processes is a reduction of the plasma cholesterol concentration.
Absorption: BAYCOL® (cerivastatin sodium tablets) is administered orally in the active form. The mean absolute bioavailability of cerivastatin following a 0.2-mg tablet oral dose is 60% (range 39 - 101%). In general, the coefficient of variation (based on the inter-subject variability) for both systemic exposure (area under the curve, AUC) and Cmax is in the 20% to 40% range. The bioavailability of cerivastatin sodium tablets is equivalent to that of a solution of cerivastatin sodium. No unchanged cerivastatin is excreted in feces. Cerivastatin exhibits linear kinetics over the dose range of 0.2 to 0.8-mg daily. In male and female patients at steady-state, the mean maximum concentrations (Cmax) following evening cerivastatin tablet doses of 0.2, 0.3, 0.4, and 0.8-mg are 2.8, 5.1, 6.2, and 12.7 µg/L, respectively. AUC values are also dose–proportional over this dose range and the mean time to maximum concentration (tmax) is approximately 2 hours for all dose strengths. Following oral administration, the terminal elimination half-life (t1/2) for cerivastatin is 2 to 4 hours. Steady-state plasma concentrations show no evidence of cerivastatin accumulation following administration of up to 0.8 mg daily.
Results from an overnight pharmacokinetic evaluation following single-dose administration of cerivastatin with the evening meal or 4 hours after the evening meal showed that administration of cerivastatin with the evening meal did not significantly alter either AUC or Cmax compared to dosing the drug 4 hours after the evening meal. In patients given 0.2 mg cerivastatin sodium once daily for 4 weeks, either at mealtime or at bedtime, there were no differences in the lipid-lowering effects of cerivastatin. Both regimens of 0.2 mg once daily were slightly more efficacious than 0.1 mg twice daily.
Distribution: The volume of distribution (VDss) is calculated to be 0.3 L/kg. More than 99% of the circulating drug is bound to plasma proteins (80% to albumin). Binding is reversible and independent of drug concentration up to 100 mg/L.
Metabolism: Biotransformation pathways for cerivastatin in humans include the following: demethylation of the pyridilic methyl ether to form M1 and hydroxylation of the methyl group in the 6'-isopropyl moiety to form M23. The combination of both reactions leads to formation of metabolite M24. The major circulating blood components are cerivastatin and the pharmacologically active M1 and M23 metabolites. The relative potencies of metabolites M1 and M23 are comparable to, but do not exceed, the potency of the parent compound. Following a 0.8-mg dose of cerivastatin to male and female patients, mean steady state Cmax values for cerivastatin, M1, and M23 were 12.7, 0.55, and 1.4 µg/L, respectively. Therefore, the cholesterol-lowering effect is due primarily to the parent compound, cerivastatin.
In vitro studies show that the hepatic cytochrome P450 (CYP) enzyme system catalyzes the cerivastatin biotransformation reactions. Specifically, two P450 enzyme sub-classes are involved. The first is CYP 2C8, which leads predominately to the major active metabolite, M23, and to a lesser extent, the other active metabolite, M1. The second is CYP 3A4, which primarily contributes to the formation of the less abundant metabolite, M1. The CYP 3A4 enzyme sub-class is also involved in the metabolism of a significant number of common drugs. The effect of the dual pathways of hepatic metabolism for cerivastatin is shown in clinical studies examining the effect of the known potent CYP 3A4 inhibitors, erythromycin and itraconazole. In these interaction studies, specific inhibition of the CYP 3A4 enzyme sub-class resulted in a 1.4- to 1.5-fold mean increase in cerivastatin plasma levels following co-treatment with erythromycin or itraconazole, possibly because of metabolism via the alternate CYP 2C8 pathway.
Excretion: Cerivastatin itself is not found in either urine or feces; M1 and M23 are the major metabolites excreted by these routes. Following an oral dose of 0.4 mg 14C-cerivastatin to healthy volunteers, excretion of radioactivity is about 24% in the urine and 70% in the feces. The parent compound, cerivastatin, accounts for less than 2% of the total radioactivity excreted. The plasma clearance for cerivastatin in humans after intravenous dosing is 12 to 13 liters per hour.
Geriatric: Plasma concentrations of cerivastatin are similar in healthy elderly male subjects ( > 65 years) and in young males ( < 40 years).
Gender: Plasma concentrations of cerivastatin in females are slightly higher than in males (approximately 12% higher for Cmax and 16% higher for AUC).
Pediatric: Cerivastatin pharmacokinetics have not been studied in pediatric patients.
Race: Cerivastatin pharmacokinetics were compared across studies in Caucasian, Japanese and Black subjects. No significant differences in AUC, Cmax, tmax, and t1/2 were found.
Renal: Steady-state plasma concentrations of cerivastatin are similar in healthy volunteers (Clcr > 90 mL/min/1.73m2) and in patients with mild renal impairment (Clcr 61-90 mL/min/1.73m2). In patients with moderate (Clcr 31-60 mL/min/1.73m2) or severe (Clcr ≤ 30 mL/min/1.73m2) renal impairment, AUC is up to 60% higher, Cmax up to 23% higher, and t1/2 up to 47% longer compared to subjects with normal renal function.
Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of cerivastatin since the drug is extensively bound to plasma proteins.
Hepatic: Cerivastatin has not been studied in patients with active liver disease (see CONTRAINDICATIONS). Caution should be exercised when BAYCOL® (cerivastatin sodium tablets) is administered to patients with a history of liver disease or heavy alcohol ingestion (see WARNINGS).
BAYCOL® (cerivastatin sodium tablets) has been studied in controlled trials in North America, Europe, Israel, and South Africa and has been shown to be effective in reducing plasma Total-C, LDL-C, VLDL-C, apo B, and TG and increasing HDL-C and apo A1 in patients with heterozygous familial and non-familial forms of hypercholesterolemia and in mixed dyslipidemia. Over 5,000 patients with Type IIa and IIb hypercholesterolemia were treated in trials of 4 to 104 weeks duration.
The effectiveness of BAYCOL® (cerivastatin (removed from market 8/2001)) in lowering plasma cholesterol has been shown in men and women, in patients with and without elevated triglycerides, and in the elderly. In four large, multicenter, placebo-controlled dose response studies in patients with primary hypercholesterolemia, BAYCOL® (cerivastatin (removed from market 8/2001)) given as a single daily dose over 8 weeks, significantly reduced Total-C, LDL-C, apo B, TG, total cholesterol/HDL cholesterol (Total-C/HDL-C) ratio and LDL cholesterol/HDL cholesterol (LDL-C/HDL-C) ratio. Significant increases in HDL-C were also observed. The median (25th and 75th percentile) percent changes from baseline in HDL-C for Baycol (cerivastatin (removed from market 8/2001)) 0.2, 0.3, 0.4, and 0.8 mg were +8 (+1, +15), +8 (+1, +14), +7 (0, +14), and +9 (+2, +16), respectively. Significant reductions in mean total-C and LDL-C were evident after one week, peaked at four weeks, and were maintained for the duration of the trial. (Pooled results at week 8 are presented in Table 1).
Table 1: Response in Patients with Primary Hypercholesterolemia
Mean Percent Change from Baseline to Week 8 Intent-To-Treat Population
| 1 - N given as a range since test results for each lipid
variable were not available in every patient
2 - Median percent change from baseline
In a pool of eight studies in patients with hypercholesterolemia and TG levels ranging from 250 mg/dL to 500 mg/dL who were treated for at least eight weeks, the following reductions in TG and increases in HDL-C were observed at Week 8 as shown in Table 2 below:
Table 2: Median Percent Change from Baseline to Week 8 in
Patients with Baseline TG between 250-500 mg/dL
|Placebo||BAYCOL® 0.2 mg||BAYCOL® 0.3 mg||BAYCOL® 0.4 mg||BAYCOL® 0.8 mg|
|1 - N given as a range since test results for each lipid variable were not available in every patient|
In a large clinical study, the number of patients meeting their National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP) II target LDL-C levels on BAYCOL® (cerivastatin (removed from market 8/2001)) 0.4 and 0.8 mg daily was assessed. The results up to 24 weeks are shown in Table 3 below:
Table 3: Percent of Patients Reaching NCEP-ATP II Goal Up
to 24 Weeks of Treatment with BAYCOL® (cerivastatin (removed from market 8/2001)) 0.4 mg and 0.8 mg
|NCEP-ATP II Treatment Guidelines||Patients Reaching LDL-C Target Up to 24 Weeks|
|Risk Factors for CHD||Baseline LDL-C (mg/dL)||Target LDL-C (mg/dL)||BAYCOL® 0.4 mg||BAYCOL® 0.8 mg|
|Baseline LDL-C Mean (mg/dL)||Percent To Goal||Baseline LDL-C Mean (mg/dL)||Percent To Goal|
|< 2 risk factors||≥ 190||< 160||234 (n=33)||79%||224 (n=156)||79%|
|≥ 2 risk factors||≥ 160||< 130||204 (n=43)||65%||201 (n=186)||72%|
|CHD||≥ 130||≤ 100||188 (n=34)||24%||187 (n=99)||53%|
Last reviewed on RxList: 4/17/2009
This monograph has been modified to include the generic and brand name in many instances.
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