Ezetimibe

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ezetimibe and Simvastatin Tablets Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and simvastatin tablets contain ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. Ezetimibe and simvastatin tablets reduce 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 reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. In a 2 week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and did not impair adrenocortical steroid hormone production. 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. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins [ see Clinical Studies ( 14 ) ]. Simvastatin Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces very-low-density lipoproteins (VLDL) and TG and increases HDL-C. 12.2 Pharmacodynamics Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. 12.3 Pharmacokinetics The results of a bioequivalence study in healthy subjects demonstrated that the ezetimibe and simvastatin 10 mg/10 mg to 10 mg/80 mg combination tablets are bioequivalent to coadministration of corresponding doses of ezetimibe and simvastatin as individual tablets. Absorption Ezetimibe After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). 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. Effect of Food on Oral Absorption Ezetimibe Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as 10 mg tablets. The C max value of ezetimibe was increased by 38% with consumption of high-fat meals. Simvastatin Relative to the fasting state, the plasma profiles of both active and total inhibitors of HMG-CoA reductase were not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal. Distribution Ezetimibe Ezetimibe and ezetimibe-glucuronide are highly bound (> 90%) to human plasma proteins. Simvastatin Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. When radiolabeled simvastatin was administered to rats, simvastatin-derived radioactivity crossed the blood-brain barrier. Metabolism and Excretion Ezetimibe Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Minimal oxidative metabolism has been observed in all species evaluated. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. 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 eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. Following oral administration of 14 C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10 day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose. Simvastatin Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is a basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Following an oral dose of 14 C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Specific Populations Geriatric Patients Ezetimibe In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2 fold higher in older (≥ 65 years) healthy subjects compared to younger subjects. Simvastatin In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18 to 30 years of age. Pediatric Patients: [ See Pediatric Use ( 8.4 ). ] Gender Ezetimibe In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (< 20%) in women than in men. Race Ezetimibe Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe was similar to those seen in Caucasian subjects. Hepatic Impairment Ezetimibe After a single 10 mg dose of ezetimibe, the mean exposure (based on area under the curve [AUC]) to total ezetimibe was increased approximately 1.7 fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe increased approximately 3 to 4 fold and 5 to 6 fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14 day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC for total ezetimibe and ezetimibe increased approximately 4 fold compared to healthy subjects. Renal Impairment Ezetimibe After a single 10 mg dose of ezetimibe in patients with severe renal disease (n = 8; mean CrCl ≤ 30 mL/min/1.73 m 2 ), the mean AUC for total ezetimibe and ezetimibe increased approximately 1.5 fold, compared to healthy subjects (n = 9). Simvastatin Pharmacokinetic studies with another statin having a similar principal route of elimination to that of simvastatin have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal impairment (as measured by creatinine clearance). Drug Interactions [ See also Drug Interactions ( 7 ). ] No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with simvastatin. No specific pharmacokinetic drug interaction studies with ezetimibe and simvastatin tablets have been conducted other than the following study with niacin extended-release tablets. Niacin: The effect of ezetimibe and simvastatin tablets (10 mg/20 mg daily for 7 days) on the pharmacokinetics of niacin extended-release tablets (1000 mg for 2 days and 2000 mg for 5 days following a low-fat breakfast) was studied in healthy subjects. The mean C max and AUC of niacin increased 9% and 22%, respectively. The mean C max and AUC of nicotinuric acid increased 10% and 19%, respectively (N = 13). In the same study, the effect of niacin extended-release tablets on the pharmacokinetics of ezetimibe and simvastatin tablets was evaluated (N = 15). While concomitant niacin extended-release tablets decreased the mean C max of total ezetimibe (1%), and simvastatin (2%), it increased the mean C max of simvastatin acid (18%). In addition, concomitant niacin extended-release tablets increased the mean AUC of total ezetimibe (26%), simvastatin (20%), and simvastatin acid (35%). Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥ 1 g/day niacin) of niacin-containing products [ see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.4 ) ]. Cytochrome P450: Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a “cocktail” study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes. In a study of 12 healthy volunteers, simvastatin at the 80 mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4 and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy. For example, cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1. Simvastatin is a substrate for CYP3A4. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [ see Warnings and Precautions ( 5.1 ); Drug Interactions ( 7.1 ) ]. Ezetimibe Table 4: Effect of Coadministered Drugs on Total Ezetimibe Coadministered Drug and Dosing Regime