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Pharmacology: Pharmacodynamics: Ezetimibe, a cholesterol absorption inhibitor, is an antilipemic agent that differs chemically and pharmacologically from other antilipemic agents. Following absorption, the drug localizes at the brush border of the small intestine and inhibits absorption of cholesterol through the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), resulting in decreased delivery of intestinal cholesterol to liver. This causes a reduction in hepatic cholesterol stores, a compensatory increase in hepatic uptake of cholesterol from systemic circulation, and consequently, an increase in systemic clearance of cholesterol. Ezetimibe does not appear to inhibit hepatic cholesterol synthesis or increase bile acid excretion.
Pharmacokinetics: Absorption: After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (Cmax) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours for ezetimibe. The effect of ezetimibe will present in approximately 2 weeks after therapy initiation. The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection.
Concomitant food administration (high fat or non-fat meals) had no effect on the oral bioavailability of ezetimibe when administered as ezetimibe can be administered with or without food.
Distribution: Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma proteins, respectively.
Metabolism: Ezetimibe is metabolized primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidation metabolism (a phase I reaction) has been observed in all species evaluated. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The half-life for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.
Excretion: Following oral administration of 14C-ezetimibe (20mg) to human subjects, total ezetimibe accounted for approximately 93% of the total radioactivity in plasma.
Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. After 48 hours, there were no detectable levels of radioactivity in the plasma.
Characteristics in Patients (Special Populations): Pediatric Patients: The pharmacokinetic of ezetimibe are similar between children ≥6 years and adults. Pharmacokinetic data in the pediatric population <6 years of age are not available.
Geriatric Patients: Plasma concentrations for total ezetimibe are about 2-fold higher in the elderly (≥65 years) than in the young (18 to 45 years). LDL-C reduction and safety profile are comparable between elderly and young subjects treated with ezetimibe. Therefore, no dosage adjustment is necessary in the elderly.
Hepatic Insufficiency: After a single 10-mg dose of ezetimibe, the mean area under the curve (AUC) for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), compared to healthy subjects. In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), the mean AUC for total ezetimibe was increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. No dosage adjustment is necessary for patients with mild hepatic insufficiency. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe (Child-Pugh score > 9) hepatic insufficiency, ezetimibe is not recommended in these patients (See PRECAUTIONS).
Renal Insufficiency: After a single 10-mg dose of ezetimibe in patients with severe renal disease, the mean AUC for total ezetimibe was increased approximately 1.5-fold, compare to healthy subjects. This result is not considered clinically significant. No dosage adjustment is necessary for renally impaired patients.
An additional patient in this study (Post-renal transplant and receiving multiple medications, including cyclosporin) had a 12-fold greater exposure to total ezetimibe.
Gender: Plasma concentrations for total ezetimibe are slightly higher (<20%) in women than in men. LDL-C reduction and safety profile are comparable between men and women treated with ezetimibe. Therefore, no dosage adjustment is necessary on the basis of gender.
