Vytorin Mechanism of Action

Vytorin 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, 2 lipid-lowering compounds with complementary mechanisms of action. Vytorin reduces elevated total cholesterol (total-C), low-density lipoprotein-C (LDL-C), apolipoprotein-B (Apo B), triglycerides (TG) and non-high-density lipoprotein-C (non-HDL-C) and increases high-density lipoprotein-C (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 (eg, statins, bile acid sequestrants [resins], fibric acid derivatives and plant stanols).
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. The molecular mechanism of action is not fully understood.
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 3-hydroxy-3-methylglutaryl CoA (HMG-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 lipoprotein (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.
Animal Pharmacology: Ezetimibe: The hypocholesterolemic effect of ezetimibe was evaluated in Rhesus monkeys, a model for the human metabolism of cholesterol, as well as in dogs. Rhesus monkeys were fed a cholesterol-containing diet that mimics a human Western diet. Ezetimibe was found to have an ED₅₀ of 0.0005 mg/kg/day for inhibiting the rise in plasma cholesterol levels (ED₁₀₀=0.003 mg/kg/day). The ED₅₀ in dogs was found to be 0.007 mg/kg/day. These results are consistent with ezetimibe being an extremely potent cholesterol absorption inhibitor.
In dogs given ezetimibe (≥0.03 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 3-fold. However, a dose of 300 mg/kg/day administered to dogs for 1 year did not result in gallstone formation or any other adverse hepatobiliary effects. In mice given ezetimibe (0.3-5 mg/kg/day) and fed a normal or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively. The relevance of these preclinical findings to humans is unknown.
Simvastatin: Simvastatin is a γ-lactone obtained by chemical modification of lovastatin. Hydrolysis of the lactone by either chemical or enzymatic means results in the dihydroxy open acid designated as β-hydroxyacid. The open acid is the active form of the compound. It is a competitive inhibitor of HMG-CoA reductase, a key rate-limiting enzyme in the cholesterol biosynthetic pathway. The K_i of inhibition of a solubilized HMG-CoA reductase preparation obtained from rat liver microsomes is approximately 1 x 10^-10 M.
Two systems have been utilized to demonstrate that simvastatin is an inhibitor of cholesterol synthesis; mammalian cells grown in culture and in vivo in the rat. The IC₅₀ values for inhibition of sterol synthesis in cultured animal cells by simvastatin, as determined by measuring the incorporation of ¹⁴C-acetate into ¹⁴C-sterol, are 19.3 nM for mouse L-M cells, 13.3 nM for the rat hepatoma cell line, H4IIE and 15.6 nM for the human hepatoma cell line, Hep-G2. These results demonstrate that simvastatin is active against the human enzyme as well as the rodent 1.
The inhibition of incorporation of ¹⁴C-acetate into ¹⁴C-cholesterol in rats has been used to assess the in vivo effectiveness of simvastatin. Simvastatin is an orally active inhibitor of cholesterol synthesis with an ID₅₀ value <0.15-0.2 mg/kg and 87% inhibition at 2.4 mg/kg by 1 hr after an oral dose of simvastatin.
Studies have been carried out in the dog in order to assess the effects of simvastatin on serum total lipoprotein cholesterol. This animal model has been shown to respond to HMG-CoA reductase inhibitors with respect to lowering of circulating cholesterol as opposed to rats, which show no sustained effects of these agents on cholesterol levels. In the dog, simvastatin is a potent, orally active agent that lowers circulating cholesterol. This occurs in the presence or absence of the bile acid sequestrant, cholestyramine.
In dogs treated with cholestyramine 12 g/day, cholesterol is decreased by an average of 35%. Treatment of these dogs with simvastatin 1 and 2 mg/kg/day results in an additional 29.1% and 37.6% decrease, respectively, from the baseline established with cholestyramine. Similarly, in chow-fed dogs, cholesterol is decreased 26.2% by treatment with simvastatin 8 mg/kg/day. The effects of simvastatin are primarily on LDL-C in spite of the fact that approximately 70-80% of circulating cholesterol in the dog is in the form of HDL. In the cholestyramine-primed dogs, LDL-C decreased by 57-72% with a 19-38% decrease in HDL.
Similarly, LDL-C decreased by 62% in chow-fed dogs after treatment with simvastatin 8 mg/kg/day with a slight decrease in HDL levels that did not reach significance.
Ancillary pharmacology studies to assess effects on organ systems and biological parameters were conducted with β-hydroxyacid. No major changes were seen. Minor effects were noted on acid secretion and respiratory parameters in dogs.
In conclusion, simvastatin is a competitive inhibitor of the key cholesterol biosynthetic enzyme, HMG-CoA reductase. This inhibition is manifested in cultured animal cells and in vivo in the rat by a block in cholesterol synthesis. In the dog, an animal model that is responsive to HMG-CoA reductase inhibitors, simvastatin is a highly effective agent for lowering circulating total-C and LDL-C. Simvastatin is free of significant effects on ancillary pharmacological parameters.
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 (C_max) occur within 1-2 hrs for ezetimibe-glucuronide and 4-12 hrs 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 <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 4 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 99.7% and 88-92% bound 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 1.3-2.4 hrs 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 10-20% and 80-90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The t_½ for ezetimibe and ezetimibe-glucuronide is approximately 22 hrs.
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 IV injection of the β-hydroxyacid metabolite, its t_½ averaged 1.9 hrs.
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 hrs, 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 hrs. The amount recovered in the feces represents absorbed drug equivalents excreted in bile as well as unabsorbed drug. Following an IV injection of the β-hydroxyacid metabolite, an average of only 0.3% of the IV dose was excreted in urine as inhibitors.
Special Populations: Characteristics in Patients: Pediatric Patients: The absorption and metabolism of ezetimibe are similar between children and adolescents (10-18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years are not available. Clinical experience in pediatric and adolescent patients (ages 9-17) has been limited to patients with homozygous familial hypercholesterolemia (HoFH).
Geriatric Patients: Plasma concentrations for total ezetimibe are about 2-fold higher in the elderly (≥65 years) than in the young (18-45 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 scores 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 scores 7-9), 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 creatinine clearance ≤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 (postrenal 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 2-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.