Zetia (Ezetimibe)
Ezetimibe
Brand Name: Zetia®
Classification:
Cardiovascular Agents
Description: Ezetimibe is a new oral antilipemic agent, approved for use as monotherapy or in combination with HMG-CoA reductase inhibitors (’statins’) for the treatment of hypercholesterolemia. Ezetimibe is the first available 2-azetidinone compound, a potent cholesterol absorption inhibitor. Ezetimibe selectively blocks the intestinal absorption of cholesterol and related phytosterols. Ezetimibe monotherapy is primarily effective in reducing total cholesterol (total-C, 13%), LDL-cholesterol (LDL-C, 18%), and Apo-B (16%) in patients with hypercholesterolemia; its effects to reduce triglycerides (8%) or to lower HDL-cholesterol (1%) are less prominent; ezetimibe typically increases HDL cholesterol (HDL-C). When used as monotherapy, ezetimibe reduces LDL-cholesterol by about 18%, compared with more potent reductions (25 - 40%) typically achieved with statin monotherapy. Combining ezetimibe with a statin results in synergistic cholesterol-lowering effects. When used in combination with 10 - 80 mg of either simvastatin or atorvastatin, combined use with ezetimibe achieves LDL reductions of approximately 51 or 56%, respectively, compared to LDL reductions of 36% with simvastatin or 44% with atorvastatin monotherapy. When used in combination with 10 - 40 mg of either pravastatin or lovastatin, combined use with ezetimibe achieves LDL reductions of approximately 39% or 40%, respectively, compared to LDL reductions of 25% with either pravastatin or lovastatin monotherapy. The adverse effect profile for combined ezetimibe/statin therapy is similar to statin monotherapy, except for an increase in the incidence of hepatic enzyme elevations observed with combined ezetimibe/statin therapy (see Adverse Reactions). Ezetimibe (Zetia®) was approved by the FDA on October 25, 2002. Combination products containing ezetimibe are also FDA approved for the treatment of hypercholesterolemia.
Mechanism of Action: Ezetimibie lowers serum cholesterol concentrations by selectively inhibiting the absorption of cholesterol and related phytosterols by the small intestine. Ezetimibe has a mechanism of action that is unique compared to other available antilipemic agents, and is complementary to that of the HMG-CoA reductase inhibitors, resulting in synergistic cholesterol-lowering effects when these drugs are used in combination. Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Ezetimibe localizes and appears to act at the brush border of the small intestine. It inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in the blood clearance of cholesterol. When ezetimibe is given as monotherapy, a compensatory increase in cholesterol synthesis occurs. With ongoing therapy, the overall effects of ezetimibe monotherapy are to reduce total cholesterol (13%), LDL-cholesterol (18%), and Apo-B (16%) in patients with hypercholesterolemia. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols (sitosterol and campesterol). In a 2 week study of 18 hypercholesterolemic patients, ezetimibe has been reported to inhibit intestinal cholesterol absorption by 54% relative to placebo.
In humans, the effects of ezetimibe to reduce triglycerides (8%) or to lower HDL-cholesterol (1%) are less prominent than its LDL-lowering effects; ezetimibe therapy usually results in increased HDL-C levels. In animal models (rodents), ezetimibe reduces the cholesterol content in chylomicrons without affecting the triglyceride content. In rodents, ezetimibe has no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins (A, D, and E), and does not impair adrenocortical steroid hormone production.
Pharmacokinetics: Ezetimibe is administered orally. Following systemic absorption, ezetimibe is extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After oral administration of a single 10 mg dose to fasting adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 - 5.5 ng/ml are attained within 4 - 12 hours. Mean peak concentrations (Cmax 45 - 71 ng/ml) of ezetimibe-glucuronide are attained within 1 - 2 hours. The absolute bioavailability of ezetimibe is not known; an injectable formulatin is not feasible due to the aqueous insolubility of ezetimibe. The apparent oral bioavailability of ezetimibe is variable; the coefficient of variation, based on intersubject variability, is 35 - 60% for AUC values. The concomitant administration of food (high-fat vs. non-fat meals) has no effect on the extent of absorption of ezetimibe. However, co-administration with a high-fat meal increases the peak concentration (Cmax) of ezetimibe by 38%. Ezetimibe and ezetimibe-glucuronide are highly bound (> 90%) to human plasma proteins.
 Zetia Tablets(Tab 10 mg)
Following absorption, ezetimibe is rapidly metabolized by glucuronidation to ezetimibe-glucuronide in the small intestine and liver. Metabolism by oxidative metabolism is minimal. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P-450 isoenzymes. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 - 20% and 80 - 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from the plasma with a half-life of about 22 hours. Ezetimibe is enterohepatically recirculated, as evidenced by multiple peaks in its plasma concentrations. Following oral administration of radiolabeled ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) accounts for approximately 93% of the total plasma radioactivity. After 48 hours, the plasma radioactivity is undetectable. Over a 10 day period, approximately 78% and 11% of the administered dose is recovered in the feces and urine, respectively. Ezetimibe is the major component recovered in the feces and accounts for 69% of the administered dose, while ezetimibe-glucuronide is the major component recovered in the urine and accounts for 9% of the administered dose.
Special Populations: Although pharmacokinetic differences have been identifed in elderly patients, women, and patients with mild hepatic impairment or severe renal impairment, no dosage adjustments for ezetimibe are indicated. Significant increases in ezetimibe exposure occur in patients with moderate to severe hepatic impairment; ezetimibe is not recommended for use in these patients. In patients with mild hepatic impairment (Child-Pugh score 5 - 6), moderate (Child Pugh score 7 - 9) or severe hepatic impairment (Child-Pugh score 10 - 15), the mean AUC values for total ezetimibe are increased approximately 1.7-fold, 3 - 4-fold, or 4-fold, respectively, compared to healthy subjects. In a multiple dose study, plasma concentrations for total ezetimibe were slightly higher (< 20%) for women relative to men. With repeated dosing for 10 days, plasma concentrations for total ezetimibe are about 2-fold higher in elderly subjects compared to younger adults; however, no dosage adjustment is recommended for elderly patients. The absorption and metabolism of ezetimibe are similar in adolescents (10 - 18 years) and adults. In 8 patients with severe renal impairment (mean CrCl < 30 ml/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe are increased by approximately 1.5-fold, compared to healthy subjects; no dosage adjustments are recommended by the manufacturer for patients with renal impairment.
References
. Sudhop T, Von Bergmann K. Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia. Drugs 2002;62:2333 - 47.
. Sudhop T, Lutjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 2002;106:1943 - 8.
. Kosoglou T, Meyer I, Veltri EP, et al. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol 2002;54:309 - 19.
. Gagne C, Gaudet D, Bruckert E, et al. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002;105:2469 - 75.
. van Heek M, Farley C, Compton DS, et al. Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function. Br J Pharmacol 2001;134:409 - 17.
. Patrick JE, Kosoglou T, Stauber KL, et al. Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects. Drug Metab Dispos 2002;30:430 - 7.
[ Revised 2/3/2006 2:58:00 PM ]
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