Edarbi

Specific antagonist of angiotensin II type 1 receptors (AT1). Azilsartan medoxomil is a prodrug. It is quickly converted into the active azilsartan molecule, which selectively prevents the development of the effects of angiotensin II by blocking its binding to AT1 receptors in various tissues. Angiotensin II is the primary vasoactive hormone of the RAAS with effects including vasoconstriction, cardiac stimulation, stimulation of aldosterone synthesis and release, and consequent renal sodium reabsorption.

Blockade of AT1 receptors inhibits the negative regulatory response of angiotensin II to renin secretion, but the resulting increase in plasma renin activity and circulating angiotensin II levels does not suppress the antihypertensive effect of azilsartan.

The antihypertensive effect of azilsartan medoxomil develops during the first 2 weeks of use with the maximum therapeutic effect achieved after 4 weeks. A reduction in blood pressure after oral administration of a single dose is usually achieved within a few hours and persists for 24 hours.

Withdrawal syndrome after sudden cessation of treatment with long-term therapy (for 6 months) with Edarbi® was not observed.

The safety and effectiveness of the drug do not depend on the age of the patients, but greater sensitivity to lowering blood pressure in some elderly patients cannot be excluded. As with other angiotensin II receptor antagonists and ACE inhibitors, the antihypertensive effect is less pronounced in black patients (usually a population with low plasma renin activity). The simultaneous use of Edarbi® 40 mg and 80 mg with dihydropyridine blockers of slow calcium channels (amlodipine) or thiazide diuretics (chlorthalidone) leads to an additional reduction in blood pressure compared to therapy with antihypertensive drugs used in monotherapy.

Influence on repolarization processes

The potential of Edarbi® to prolong the QT/QTc interval was assessed in healthy volunteers during a QT/QTc study. When using the drug Edarbi® at a dose of 320 mg, no increase in the QT/QTc interval was noted. QTc — corrected (relative to heart rate) value of the QT interval, relative value. Because The duration of the QT interval depends on the heart rate (lengthening as it slows down); to assess it, it must be corrected for heart rate. Prolongation of the QT interval reflects the heterogeneity of the processes of repolarization of the ventricular myocardium, and is regarded as an independent indicator indicating the possibility of fatal cardiac arrhythmias.

Pharmacokinetics

Suction

The estimated absolute bioavailability of azilsartan medoxomil when administered orally is approximately 60% based on plasma concentration profiles. Cmax of azilsartan in blood plasma is achieved on average within 1.5-3 hours after taking the drug orally. Food intake does not affect the bioavailability of azilsartan.

Distribution

The pharmacokinetics of azilsartan medoxomil is dose proportional over a dose range of 20 mg to 320 mg after single or multiple oral administration.

Vd of azilsartan is about 16 l. Azilsartan binds to plasma proteins (more than 99%), mainly to albumin. Plasma protein binding remains constant when azilsartan plasma concentrations are significantly higher than the range achieved when taken at recommended doses. Css of azilsartan is achieved within 5 days; its accumulation in the blood plasma does not occur with daily use once a day.

Animal studies with radioactive tracers have shown that the amount of azilsartan that penetrates the BBB is minimal.

Metabolism

After oral administration during absorption from the gastrointestinal tract, azilsartan medoxomil is converted into the pharmacologically active metabolite azilsartan under the action of the enzyme carboxymethylenebutenolidase in the intestines and liver. Azilsartan is metabolized to two primary metabolites primarily in the liver. The main metabolite in blood plasma is formed by O-dealkylation and is designated as metabolite M-II, the minor metabolite is formed by decarboxylation and is designated as metabolite MI. The AUC values for these metabolites in humans are respectively 50% and less than 1% compared to azilsartan. MI and M-II do not affect the pharmacological activity of Edarbi®. The main enzyme responsible for the metabolism of azilsartan is the CYP2C9 isoenzyme.

Removal

Azilsartan and its metabolites are excreted from the body, both through the intestines and the kidneys. Studies have shown that after oral administration of azilsartan medoxomil, about 55% (mainly as the metabolite MI) is found in the feces and about 42% (15% as azilsartan, 19% as the metabolite M-II) in the urine. T1/2 of azilsartan is about 11 hours, renal clearance is about 2.3 ml/min.

Pharmacokinetics in special groups of patients

The pharmacokinetics of azilsartan in children and adolescents under 18 years of age have not been studied.

The pharmacokinetics of azilsartan in young patients (18-45 years) and elderly patients (65-85 years) are not significantly different.

In patients with mild, moderate and severe renal impairment, AUC was increased by 30%, 25% and 95%, respectively. No increase in AUC (5%) was observed in patients with end-stage renal disease on hemodialysis. Clinical data on pharmacokinetics in patients with severe or end-stage renal failure are not available. Azilsartan is not removed from the systemic circulation by hemodialysis.

Use of Edarbi® for more than 5 days in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) severity of liver failure leads to a slight increase in AUC (1.3-1.6 times, respectively). The pharmacokinetics of Edarbi® in patients with severe (class C on the Child-Pugh scale) degree of liver failure have not been studied.

The pharmacokinetics of azilsartan in men and women is not significantly different. No dose adjustment is required depending on gender.

The pharmacokinetics of azilsartan do not differ significantly depending on the race of patients. No dose adjustment is required based on race.

Edarbi®

Suction

Azilsartan medoxomil is a prodrug. After oral administration, it is converted to the pharmacologically active metabolite azilsartan during absorption from the gastrointestinal tract under the action of the enzyme carboxymethylenebutenolidase in the intestine and liver.

The estimated absolute bioavailability of azilsartan medoxomil when administered orally is approximately 60% based on plasma concentration profiles.

The maximum concentration (Cmax) of azilsartan in blood plasma is on average reached within 1.5-3 hours after taking the drug orally.

Food intake does not affect the bioavailability of azilsartan.

Distribution

The volume of distribution of azilsartan is about 16 liters. Azilsartan binds to blood plasma proteins (more than 99%), mainly to blood plasma albumin. The binding to plasma proteins remains constant when the concentration of azilsartan in the blood plasma significantly exceeds the range achieved when taking recommended doses.

There are no data on the use of the drug during pregnancy and breastfeeding. Azilsartan crosses the placenta of pregnant rats and is excreted into the milk of lactating rats (see section Use during pregnancy and breastfeeding).

Radiolabeled animal studies have shown that the amount of azilsartan that crosses the blood-brain barrier is minimal.

Metabolism

Azilsartan is metabolized to two primary metabolites primarily in the liver. The main metabolite in blood plasma is formed by O-dealkylation and is designated as metabolite M-II, the minor metabolite is formed by decarboxylation and is designated as metabolite M-I. The AUC (area under the concentration-time pharmacokinetic curve) values for these metabolites in humans are respectively 50% and less than 1% compared to azilsartan. M-I and M-II do not affect the pharmacological activity of Edarbi®. The main enzyme responsible for the metabolism of azilsartan is the CYP2C9 isoenzyme.

Removal

Azilsartan and its metabolites are excreted from the body, both through the intestines and the kidneys. Studies have shown that after oral administration of azilsartan medoxomil, about 55% (mainly in the form of metabolite M-I) is found in the feces and about 42% (15% in the form of azilsartan, 19% in the form of metabolite M-II) in urine .

The half-life of azilsartan is about 11 hours and the renal clearance is about 2.3 ml/min.

The equilibrium concentration of azilsartan is achieved within 5 days and its accumulation in the blood plasma does not occur with a single daily use.

Linearity/Nonlinearity

The pharmacokinetics of azilsartan in azilsartan medoxomil are dose proportional over a dose range of 20 mg to 320 mg following single or multiple oral doses.

Pharmacokinetics in special groups

Children

The pharmacokinetics of azilsartan in children under 18 years of age has not been studied.

Elderly patients

The pharmacokinetics of azilsartan in young (18-45 years) and elderly (65-85 years) patients does not differ significantly.

Kidney failure

In patients with mild, moderate and severe renal impairment, AUC was increased by +30%, +25% and +95%, respectively. No increase (+5%) in AUC was observed in patients with end-stage renal disease on hemodialysis. Clinical data on pharmacokinetics in patients with severe or end-stage renal failure are not available.

Azilsartan is not removed from the systemic circulation by hemodialysis.

Liver failure

The pharmacokinetics of Edarbi® in patients with severe (class C on the Child-Pugh scale) degree of liver failure have not been studied.

Gender

The pharmacokinetics of azilsartan in men and women is not significantly different. No dose adjustment is required depending on gender.

Race

The pharmacokinetics of azilsartan do not differ significantly depending on the race of patients. No dose adjustment is required based on race.

Edarbi® Klo

Edarbi® Clo is a combination drug that contains an angiotensin II receptor antagonist (azilsartan medoxomil) and a thiazide-like diuretic (chlorthalidone). The simultaneous use of two active substances leads to a more pronounced decrease in blood pressure (BP) compared to taking each of them in monotherapy. When taking the drug once a day, an effective reduction in blood pressure is achieved within 24 hours.

Azilsartan medoxomil , one of the active ingredients of the drug Edarbi® Clo, is a specific antagonist of angiotensin II type 1 receptors (AT1). Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the main vasoconstrictor factor of the RAAS (renin-angiotensin-aldosterone system), its actions include vasoconstriction, stimulation of aldosterone synthesis and secretion, increased heart rate (HR) and renal sodium reabsorption.

Azilsartan medoxomil is an oral prodrug. Azilsartan medoxomil is rapidly converted to the active azilsartan molecule, which selectively inhibits the effects of angiotensin II by blocking its binding to AT1 receptors in various tissues, such as vascular smooth muscle and the adrenal glands. Therefore, its action is not related to the angiotensin II biosynthetic pathway.

The AT2 receptor is also found in many tissues, but its role in regulating the activity of the cardiovascular system is not fully understood. The affinity of azilsartan for the AT1 receptor is 10,000 times higher than for the AT2 receptor.

Inhibition of RAAS activity through ACE inhibitors, which suppress the formation of angiotensin II from angiotensin I, is widely used in the treatment of arterial hypertension. ACE inhibitors also suppress the breakdown of bradykinin, which is catalyzed by ACE. Since azilsartan does not inhibit ACE (kininase II), it should not affect bradykinin activity.

Azilsartan does not bind to or block other receptors or ion channels that play an important role in the regulation of the cardiovascular system. Azilsartan dose-dependently suppresses the vasoconstrictor effects of angiotensin II infusion. A single dose of azilsartan at a dose equivalent to 32 mg of azilsartan medoxomil suppressed the maximum vasoconstrictor effect of angiotensin II by approximately 90% at the time of highest concentration, and by approximately 60% 24 hours after administration. In healthy volunteers, plasma concentrations of angiotensin I and angiotensin II and renin activity increased, and aldosterone concentrations decreased after a single oral dose and after repeated doses of azilsartan medoxomil; No clinically significant effect on serum potassium or sodium levels was detected. In general, the pharmacodynamic properties of azilsartan medoxomil are consistent with blocking the AT1 receptor.

Chlorthalidone , a thiazide-like diuretic, inhibits the active reabsorption of sodium ions in the renal tubules (the initial part of the distal convoluted tubule of the nephron), increasing the excretion of sodium and chloride ions and increasing diuresis. In addition, chlorthalidone increases the excretion of potassium, magnesium and bicarbonate ions, and retains calcium ions and uric acid.

The antihypertensive effect of chlorthalidone is associated with the removal of fluid and sodium from the body.

The diuretic effect develops 2-3 hours after taking chlorthalidone orally and persists for 2-3 days.

The antihypertensive effect of chlorthalidone develops gradually with the maximum therapeutic effect achieved 2-4 weeks after the start of therapy.

In clinical trials, the combination of azilsartan medoxomil/chlorthalidone was more effective than the combination of azilsartan medoxomil with hydrochlorothiazide or the combination of olmesartan medoxomil/hydrochlorothiazide, although a higher proportion of study participants in the comparison group required a dose increase due to insufficient blood pressure (BP) control.

In a double-blind, 12-week dose-escalation study, azilsartan medoxomil/chlorthalidone 40 mg/25 mg was statistically significantly superior to olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg in reducing systolic blood pressure in moderate to severe hypertension. Similar results were obtained in all patient subgroups, regardless of age, gender or race.

The combination of azilsartan medoxomil/chlorthalidone lowered blood pressure more effectively than the combination of olmesartan medoxomil/hydrochlorothiazide in each hour of the 24-hour interval between doses of drugs, according to ABPM (24-hour blood pressure monitoring).