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THERAPEUTIC CLASS: VYTORIN (ezetimibe/simvastatin) is a lipid-lowering product that selectively inhibits the intestinal absorption of cholesterol and related plant sterols and inhibits the endogenous synthesis of cholesterol.
PHARMACOLOGY: Mechanism of Action: VYTORIN: Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. VYTORIN contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. VYTORIN reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis.
Ezetimibe: Ezetimibe inhibits the intestinal absorption of cholesterol. Ezetimibe is orally active and has a mechanism of action that differs from other classes of cholesterol-reducing compounds (e.g., statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols.
Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction.
In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo.
A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.
Simvastatin: After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active β-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3-hydroxy-3-methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.
Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolized predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of simvastatin may involve both reduction of VLDL-cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with simvastatin. In addition, simvastatin moderately increases HDL-C and reduces plasma TG. As a result of these changes, the ratios of total- to HDL-C and LDL- to HDL-C are reduced.
Pharmacokinetics: Absorption: Ezetimibe: After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a 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 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 10-mg tablets.
Simvastatin: The availability of the β-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose, consistent with extensive hepatic first-pass extraction. The major metabolites of simvastatin present in human plasma are the β-hydroxyacid and four additional active metabolites.
Relative to the fasting state, the plasma profiles of both active and total inhibitors were not affected when simvastatin was administered immediately before a test meal.
Distribution: Ezetimibe: Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma proteins, respectively.
Simvastatin: Both simvastatin and the β-hydroxyacid are bound to human plasma proteins (95%).
The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of drug occurred after multiple dosing. In all of the previously mentioned pharmacokinetic studies, the maximum plasma concentration of inhibitors occurred 1.3 to 2.4 hours post-dose.
Metabolism: Ezetimibe: Ezetimibe is metabolized primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidative 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.
Simvastatin: Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.
In man simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is its primary site of action, with subsequent excretion of drug equivalents in the bile. Consequently, availability of active drug to the systemic circulation is low.
Following an intravenous injection of the β-hydroxyacid metabolite, its half-life averaged 1.9 hours.
Elimination: Ezetimibe: Following oral administration of 14C-ezetimibe (20 mg) 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.
Simvastatin: Following an oral dose of radioactive simvastatin to man, 13% of the radioactivity was excreted in the urine and 60% in the feces within 96 hours. The amount recovered in the feces represents absorbed drug equivalents excreted in bile as well as unabsorbed drug. Following an intravenous injection of the β-hydroxyacid metabolite an average of only 0.3% of the IV dose was excreted in urine as inhibitors.
Characteristics in Patients [Special Populations]: Pediatric Patients: The absorption and metabolism of ezetimibe are similar between children and adolescents (10 to 18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 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.
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 or 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: Ezetimibe: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m2), the mean AUC for total ezetimibe was increased approximately 1.5-fold, compared to healthy subjects (n=9).
An additional patient in this study (post-renal transplant and receiving multiple medications, including cyclosporine) had a 12-fold greater exposure to total ezetimibe.
Simvastatin: In a study of patients with severe renal insufficiency (creatinine clearance <30 mL/min), the plasma concentrations of total inhibitors after a single dose of a related HMG-CoA reductase inhibitor were approximately two-fold higher than those in healthy volunteers.
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.
Race: Based on a meta-analysis of pharmacokinetic studies with ezetimibe, there were no pharmacokinetic differences between Blacks and Caucasians.
Drug Interactions: Diltiazem: In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7-fold increase in exposure of simvastatin acid, presumably due to inhibition of CYP3A4.
Amlodipine: In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid.
