Cerivastatin pharmacokinetics and molecular data

Pharmacokinetics
Absorption Distribution Metabolism Excretion Special populations
 * Half-life
 * Effect of food
 * Dual pathway metabolism
 * Geriatric
 * Gender
 * Pediatric
 * Race
 * Renal
 * Hemodialysis
 * Hepatic

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. Return to top

Half-life
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. Return to top

Effect of food
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. Return to top

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. Return to top

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. Return to top

Dual pathway metabolism
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 cotreatment with erythromycin or itraconazole, possibly because of metabolism via the alternate CYP 2C8 pathway. Return to top

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. Return to top

Geriatric
Plasma concentrations of cerivastatin are similar in healthy elderly male subjects (>65 years) and in young males (<40 years). Return to top

Gender
Plasma concentrations of cerivastatin in females are slightly higher than in males (approximately 12% higher for Cmax and 16% higher for AUC). Return to top

Pediatric
Cerivastatin pharmacokinetics have not been studied in pediatric patients. Return to top

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. Return to top

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. Return to top

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. Return to top

Hepatic
Cerivastatin has not been studied in patients with active liver disease. Caution should be exercised when BAYCOL® (cerivastatin sodium tablets) is administered to patients with a history of liver disease or heavy alcohol ingestion. Return to top