Ezomib Mechanism of Action

Pharmacotherapeutic group: Lipid modifying agents, Other lipid modifying agents. ATC code: C10A X09.
PHARMACOLOGY: Pharmacodynamics: Ezomib is in new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related plant sterols. Ezomib 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 localises 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 hypercholesterolaemic 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 fat soluble vitamins A and D.
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. A beneficial effect of ezetimibe on cardiovascular morbidity and mortality has not yet been demonstrated.
Pharmacokinetics: Absorption: 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 Ezomib 10 mg tablets. Ezomib can be administered with or without food.
Distribution: Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma proteins, respectively.
Biotransformation: Ezetimibe is metabolised 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.
Elimination: 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 faeces and urine, respectively, over a 10-day collection period. After 48 hours, there were no detectable levels of radioactivity in the plasma.
Paediatric population: 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 paediatric population <10 years of age are not available. Clinical experience in paediatric and adolescent patients includes patients with HoFH, HeFH, or sitosterolaemia.
Elderly: 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. Therefore, no dosage adjustment is necessary in the elderly.
Hepatic impairment: After a single 10 mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic insufficiency (Child Pugh score 5 or 6), compared to a 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 dose 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, Ezomib is not recommended in these patients (see Precautions).
Renal impairment: 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). This result is not considered clinically significant. No dosage adjustment is necessary for renally impaired patients.
An additional patient in this study (post-renal transplant and receiving multiple medications, including ciclosporin) had a 12-fold greater exposure to total ezetimibe.
Gender: Plasma concentrations for total ezetimibe are slightly higher (approximately 20%) in women than in men.
LDL-C reduction and safety profile are comparable between men and women treated with ezetimibe. Therefore, no dosage adjustment is necessary on the basis of gender.
Toxicology: Preclinical safety data: Animal studies on the chronic toxicity of ezetimibe identified no target organs for toxic effects. In dogs treated for four weeks with ezetimibe (≥ 0.03 mg/kg/day) the cholesterol concentration in the cystic bile was increased by a factor of 2.5 to 3.5. However, in a one-year study on dogs given doses of up to 300 mg/kg/day no increased incidence of cholelithiasis or other hepatobiliary effects were observed. The significance of these data for humans is not known. A lithogenic risk associated with the therapeutic use of Ezomib cannot be ruled out.
In co-administration studies with ezetimibe and statins the toxic effects observed were essentially those typically associated with statins. Some of the toxic effects were more pronounced than observed during treatment with statins alone. This is attributed to pharmacokinetic and pharmacodynamic interactions in co-administration therapy. No such interactions occurred in the clinical studies. Myopathies occurred in rats only after exposure to doses that were several times higher than the human therapeutic dose (approximately 20 times the AUC level for statins and 500 to 2,000 times the AUC level for the active metabolites).
In a series of in vivo and in vitro assays ezetimibe, given alone or co-administered with statins, exhibited no genotoxic potential. Long-term carcinogenicity tests on ezetimibe were negative.
Ezetimibe had no effect on the fertility of male or female rats, nor was it found to be teratogenic in rats or rabbits, nor did it affect prenatal or postnatal development. Ezetimibe crossed the placental barrier in pregnant rats and rabbits given multiple doses of 1,000 mg/kg/day. The co-administration of ezetimibe and statins was not teratogenic in rats. In pregnant rabbits a small number of skeletal deformities (fused thoracic and caudal vertebrae, reduced number of caudal vertebrae) were observed. The co-administration of ezetimibe with lovastatin resulted in embryolethal effects.