Ezetrol®
Preclinical studies have shown that ezetimibe does not induce cytochrome P450 isoenzymes. No clinically significant pharmacokinetic interactions were observed between ezetimibe and drugs that are metabolized by cytochrome P450 isoenzymes 1A2, 2D6, 2C8, 2C9 and 3A4 or N-acetyltransferase.
Ezetimibe has no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, midazolam and warfarin.
Concomitant use of cimetidine with ezetimibe does not affect the bioavailability of the latter.
Concomitant use of antacids reduces the rate of absorption of ezetimibe, but does not affect its bioavailability and, therefore, the decrease in the rate of absorption is not clinically significant.
When used concomitantly with cholestyramine, the AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) is reduced by approximately 55%. The additional reduction in LDL-C due to the addition of ezetimibe to cholestyramine may be reduced by this interaction.
In patients who underwent kidney transplantation with creatinine clearance more than 50 ml/min, constantly receiving cyclosporine, a single dose of Ezetrol at a dose of 10 mg was accompanied by an average 3.4-fold (from 2.3 to 7.9 times) increase in the AUC of ezetimibe. One patient who underwent a kidney transplant and had severe renal failure (creatinine clearance 13.2 ml/min/1.73 m2) who received complex therapy including cyclosporine had a 12-fold increase in ezetimibe concentrations compared with the control group. In 12 healthy volunteers who received ezetimibe at a dose of 20 mg/day for 8 days simultaneously with cyclosporine at a daily dose of 100 mg, on the 7th day an increase in the AUC of cyclosporine by an average of 15% was detected (from a decrease of 10% to an increase of 50%) compared with patients in whom cyclosporine was used as monotherapy at a dose of 100 mg/day.
Concomitant use of fenofibrate or gemfibrozil increases the total concentration of ezetimibe by approximately 1.5 and 1.7 times, respectively. However, this increase is not considered clinically significant.
The safety and effectiveness of ezetimibe when used with fibrates has not been established. Fibrates can increase the release of cholesterol into bile, which can lead to gallstones. In preclinical studies in dogs, ezetimibe increased cholesterol levels in the gallbladder. Although the significance of these data in humans is unknown, coadministration of Ezetrol with fibrates is not recommended prior to clinical trials.
When Ezetrol was taken concomitantly with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin and rosuvastatin, no clinically significant pharmacokinetic interaction was observed.
Instructions for use EZETROL® (EZETROL)
Suction
After oral administration, ezetimibe is rapidly absorbed and extensively conjugated in the small intestine and liver to form a pharmacologically active phenolic glucuronide (ezetimibe glucuronide). Cmax of ezetimibe glucuronide is achieved after 1-2 hours, ezetimibe - after 4-12 hours. The absolute bioavailability of ezetimibe cannot be determined, since this compound is practically insoluble in water.
Concomitant ingestion of food (both high-fat and low-fat) does not affect the bioavailability of ezetimibe when taken orally at a dose of 10 mg.
Distribution
Plasma protein binding of ezetimibe and ezetimibe glucuronide is 99.7% and 88-92%, respectively.
Metabolism
Ezetimibe is metabolized primarily in the small intestine and liver by conjugation with a glucuronide (phase II reaction) followed by excretion in the bile. Minimal oxidative metabolism (phase I reaction) is observed in all species studied. Ezetimibe and ezetimibe glucuronide are the main substances detected in plasma, accounting for approximately 10-20% and 80-90% of the total drug content in plasma, respectively. Ezetimibe and ezetimibe glucuronide are slowly cleared from plasma under conditions of intensive enterohepatic recirculation.
Removal
After oral administration of 20 mg of 14C-labeled ezetimibe, the level of total ezetimibe in the blood plasma was 93% of the total radioactivity of the blood plasma. After 48 hours, radioactive products of the drug were not detected in the blood plasma.
T1/2 of ezetimibe and ezetimibe glucuronide is about 22 hours.
Within 10 days, about 78% of the total dose taken is excreted in feces and about 11% in urine.
Pharmacokinetics in special clinical situations
Absorption and metabolism of ezetimibe are similar in children, adolescents aged 10-18 years and adults. Based on measurements of total ezetimibe concentrations, pharmacokinetic parameters did not differ between adolescents and adults. Pharmacokinetic data for children under 10 years of age are not available.
In elderly patients over the age of 65 years, the plasma concentration of total ezetimibe is approximately 2 times higher than in young patients (from 18 to 45 years). The degree of reduction in LDL-C levels and the safety profile are comparable in elderly and young patients receiving Ezetrol®.
After a single dose of 10 mg, the average AUC for total ezetimibe in patients with mild hepatic impairment (Child-Pugh score 5-6) increases approximately 1.7 times compared to healthy volunteers. No dose adjustment is required for patients with mild hepatic impairment.
In a 14-day study of ezetimibe 10 mg/day in patients with moderate hepatic impairment (Child-Pugh score 7-9), the AUC for total ezetimibe was approximately 4 times greater than in patients with normal hepatic function. , both on the 1st day and on the 14th day of the study.
After a single dose of ezetimibe at a dose of 10 mg in patients with severe kidney disease (n=8) (CrCl not more than 30 ml/min/1.73 m2), the AUC for total ezetimibe increased approximately 1.5-fold compared to healthy volunteers (n=9) . This result is not clinically significant. No dose adjustment is required for patients with impaired renal function.
Plasma concentrations of ezetimibe are slightly higher (20%) in women than in men. The LDL-C reduction and safety profile are similar in women and men treated with ezetimibe.
Ezetrol
Lipid-lowering drug for oral administration. Selectively inhibits the absorption of cholesterol and some plant styrenes in the intestine. The mechanism of action of ezetimibe differs from that of other classes of lipid-lowering agents (eg, statins, bile acid sequestrants, fibrates, and plant styrenes).
When entering the small intestine, ezetimibe is localized in the brush border of the small intestine and interferes with the absorption of cholesterol (C), which leads to a decrease in the supply of C from the intestine to the liver, thereby reducing the reserves of C in the liver and increasing the removal of C from the blood. Ezetrol® does not increase the excretion of bile acids (unlike drugs that bind bile acids) and does not inhibit the synthesis of cholesterol in the liver (unlike statins). In a two-week clinical study that included 18 patients with hypercholesterolemia, Ezetrol® reduced the absorption of cholesterol in the intestine by 54% compared to placebo.
Statins reduce the synthesis of cholesterol in the liver. Due to two different mechanisms of action, drugs of these two classes, when administered together, provide an additional reduction in cholesterol levels. Ezetrol®, prescribed in combination with statins, reduces total cholesterol, LDL-C, apolipoprotein-B and triglycerides and increases HDL-C in patients with hypercholesterolemia to a greater extent than ezetimibe or simvastatin, prescribed separately.
Clinical studies have shown that elevated levels of total cholesterol, LDL cholesterol, and apolipoprotein B, the main protein component of LDL, contribute to the development of atherosclerosis. In addition, reduced HDL-C levels are associated with the development of atherosclerosis. Epidemiological studies have established that cardiovascular morbidity and mortality are directly related to the level of total cholesterol and LDL cholesterol and inversely related to the level of HDL cholesterol. Like LDL, lipoproteins rich in cholesterol and triglycerides, including VLDL, LDLP and remnant, can also contribute to the development of atherosclerosis.
A series of preclinical studies were conducted to determine the selectivity of ezetimibe in inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14C-cholesterol and had no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, and fat-soluble vitamins.
Pharmacokinetics
Suction
After oral administration, ezetimibe is rapidly absorbed and extensively conjugated in the small intestine and liver to form a pharmacologically active phenolic glucuronide (ezetimibe glucuronide). Cmax of ezetimibe glucuronide is achieved after 1-2 hours, ezetimibe - after 4-12 hours. The absolute bioavailability of ezetimibe cannot be determined, since this compound is practically insoluble in water.
Concomitant ingestion of food (both high-fat and low-fat) does not affect the bioavailability of ezetimibe when taken orally at a dose of 10 mg.
Distribution
Plasma protein binding of ezetimibe and ezetimibe glucuronide is 99.7% and 88-92%, respectively.
Metabolism
Ezetimibe is metabolized primarily in the small intestine and liver by conjugation with a glucuronide (phase II reaction) followed by excretion in the bile. Minimal oxidative metabolism (phase I reaction) is observed in all species studied. Ezetimibe and ezetimibe glucuronide are the main substances detected in plasma, accounting for approximately 10-20% and 80-90% of the total drug content in plasma, respectively. Ezetimibe and ezetimibe glucuronide are slowly cleared from plasma under conditions of intensive enterohepatic recirculation.
Removal
After oral administration of 20 mg of 14C-labeled ezetimibe, the level of total ezetimibe in the blood plasma was 93% of the total radioactivity of the blood plasma. After 48 hours, radioactive traces of the drug were not detected in the blood plasma.
T1/2 of ezetimibe and ezetimibe glucuronide is about 22 hours.
Within 10 days, about 78% of the total dose taken is excreted in feces and about 11% in urine.
Pharmacokinetics in special clinical situations
Pharmacokinetic data for children under 10 years of age are not available. Absorption and metabolism of ezetimibe are similar in children, adolescents aged 10-18 years and adults. Based on measurements of total ezetimibe concentrations, pharmacokinetic parameters did not differ between adolescents and adults.
In elderly patients over the age of 65 years, the plasma concentration of total ezetimibe is approximately 2 times higher than in young patients (from 18 to 45 years). The degree of reduction in LDL-C levels and the safety profile are comparable in elderly and young patients receiving Ezetrol®.
After a single dose of 10 mg, the average AUC for total ezetimibe in patients with mild hepatic impairment (Child-Pugh score 5-6) increases approximately 1.7 times compared to healthy volunteers. No dose adjustment is required for patients with mild hepatic impairment.
In a 14-day study of ezetimibe at a dose of 10 mg/day in patients with moderate hepatic impairment (Child-Pugh score 7-9), the AUC for total ezetimibe was approximately 4-fold greater compared with healthy volunteers as 1-fold. th day, and on the 14th day of the study.
After a single dose of ezetimibe at a dose of 10 mg in patients with severe kidney disease (n=8) (CrCl not more than 30 ml/min/1.73 m2), the AUC for total ezetimibe increased approximately 1.5-fold compared to healthy volunteers (n=9) . This result is not clinically significant. No dose adjustment is required for patients with impaired renal function.
Plasma concentrations of ezetimibe are slightly higher (less than 20%) in women than in men. The reduction in LDL-C levels and the safety profile are comparable in patients of both sexes treated with ezetimibe. Therefore, no dose adjustment is required for men or women.
