Edarbyclor

Edarbyclor Mechanism of Action

Manufacturer:

Celltrion Healthcare

Distributor:

Zuellig Pharma
Full Prescribing Info
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Pharmacology: Pharmacodynamics: Mechanism of Action: The active ingredients of Edarbyclor target two separate mechanisms involved in blood pressure regulation. Azilsartan blocks the vasoconstriction and sodium retaining effects of angiotensin II on cardiac, vascular smooth muscle, adrenal and renal cells. Chlorthalidone produces diuresis with increased excretion of sodium and chloride at the cortical diluting segment on the ascending limb of henle's loop of the nephron.
Azilsartan Medoxomil: Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzymes (ACE, kinase II). Angiotensin II is the principle pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Azilsartan blocks the vasoconstriction and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathway for angiotensin II synthesis.
An AT2 receptor is also found in many tissues, but the receptor is not known to be associated with cardiovascular homeostasis. Azilsartan has more than 10,000-fold greater affinity for the AT1 receptor than for the AT2 receptor.
Blockade of the renin-agiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction catalyzed by ACE. Because azilsartan does not inhibit ACE (kinase II), it should not affect bradykinin levels. Whether this difference has clinical relevance is not yet known. Azilsartan does not bind to or block other receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of azilsartan on blood pressure.
Chlorthalidone: Chlorthalidone produces diuresis with increased excretion of sodium and chloride. The site of action appears to be the cortical diluting segment of the ascending limb of Henle's loop of the nephron. The diuretic effects of chlorthalidone lead to decreased extracellular fluid volume, plasma volume, cardiac output, total exchangeable sodium, glomerular filtration rate and renal plasma flow. Although the mechanism of action of chlorthalidone and related drugs is not wholly clear, sodium and water depletion appear to provide a basis for its antihypertensive effect.
Edarbyclor: Edarbyclor tablets have been shown to be effective in lowering blood pressure. Both azilsartan medoxomil and chlorthalidone lower blood pressure by reducing peripheral resistance but through complementary mechanisms.
Azilsartan Medoxomil: Azilsartan inhibits the pressor effects of an angiotensin II infusion in a dose-related manner. An azilsartan single dose equivalent to azilsartan medoxomil 32 mg inhibited the maximal pressor effect by approximately 90% at peak, and approximately 60% at 24 hours. Plasma angiotensin I and II concentrations and plasma renin activity increased while plasma aldosterone concentrations decreased after single and repeated administration of azilsartan medoxomil to healthy subjects; no clinically significant effects on serum potassium or sodium were observed.
Chlorthalidone: The diuretic effect of chlorthalidone occurs in approximately 2.6 hrs and continues for up to 72 hours.
Clinical Studies: The antihypertensive effects of Edarbyclor have been demonstrated in a total of 5 randomized controlled studies, which included 4 double-blind, active-controlled studies and 1 open-label, long-term active-controlled study. The studies ranged from 8 weeks to 12 months in duration, at doses ranging from 20/12.5 mg to 80/25 mg once daily. A total of 5,310 patients (3,082 given Edarbyclor and 2,228 given active comparator) with moderate or severe hypertension were studied. Overall, randomized patients had a mean age of 57 years, and included 52% males, 72% whites, 21% blacks, 15% with diabetes, 70% with mild or moderate renal impairment, and a mean BMI of 31.6 kg/m2.
An 8-week, multi-center, randomized, double-blind, active-controlled, parallel group factorial trial in patients with moderate to severe hypertension compared the effect on blood pressure of Edarbyclor with the respective monotherapies. The trial randomized 1,714 patients with baseline systolic blood pressure between 160 and 190 mmHg (mean 165 mmHg) and a baseline diastolic blood pressure <119 mmHg (mean 95 mmHg) to one of the 11 active treatment arms.
The 6 treatment combinations of azilsartan medoxomil 20, 40 or 80 mg and chlorthalidone 12.5 or 25 mg resulted in statistically significant reduction in systolic and diastolic blood pressure as determined by ambulatory blood pressure monitoring (ABPM) (Table 1) and clinic measurement (Table 2) at trough compared with the respective individual monotherapies. The clinic blood pressure reductions appear larger than those observed with ABPM, because the former include a placebo effect, which was not directly measured. Most of the antihypertensive effect of Edarbyclor occurs within 1-2 weeks of dosing. The blood pressure lowering effect was maintained throughout the 24-hour period (see Tables 1, 2 and Figure 1).

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Edarbyclor was effective in reducing blood pressure regardless of age, gender, or race.
Edarbyclor was effective in treating black patients (usually a low-renin population).
In a 12-week, double-blind forced-titration trial, Edarbyclor 40/25 mg was statistically superior (P<0.001) to olmesartan medoxomil-hydrochlorothiazide (OLM/HCTZ) 40/25 mg in reducing systolic blood pressure in patients with moderate to severe hypertension (Table 3). Similar results were observed in all subgroups, including age, gender or race of patients. (See Table 3.)

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Edarbyclor lowered blood pressure more effectively than OLM/HCTZ at each hour of the 24-hour interdosing period as measured by ABPM.
Cardiovascular Outcomes: There are no trials of Edarbyclor demonstrating reductions in cardiovascular risk in patients with hypertension; however, trials with chlorthalidone and at least one drug pharmacologically similar to azilsartan medoxomil have demonstrated such benefits.
Pharmacokinetics: Edarbyclor: Following oral administration of Edarbyclor, peak plasma concentrations of azilsartan and chlorthalidone are reached at 3 and 1 hours, respectively. The rate (Cmax and Tmax) and extent (AUC) of absorption of azilsartan are similar when it is administered alone or with chlorthalidone. The extent (AUC) of absorption of chlorthalidone is similar when it is administered alone or with azilsartan medoxomil; however, the Cmax of chlorthalidone from Edarbyclor was 47% higher. The elimination half-lives of azilsartan and chlorthalidone are approximately 12 hours and 45 hours, respectively.
There is no clinically significant effect of food on the bioavailability of Edarbyclor.
Azilsartan Medoxomil: Absorption: Azilsartan medoxomil is rapidly hydrolyzed to azilsartan, the active metabolite, in the gastrointestinal tract during absorption. Azilsartan medoxomil is not detected in plasma after oral administration. Dose proportionality in exposure was established for azilsartan in the azilsartan medoxomil dose range of 20 mg to 320 mg after single or multiple dosing.
The estimated absolute bioavailability of azilsartan following administration of azilsartan medoxomil is approximately 60%. After oral administration of azilsartan medoxomil, peak plasma concentration (Cmax) of azilsartan are reached within 1.5 to 3 hours. Food does not affect the bioavailability of azilsartan.
Distribution: Azilsartan Medoxomil: The volume of distribution of azilsartan is approximately 16 L. Azilsartan is highly bound to human plasma proteins (>99%), mainly serum albumin. Protein-binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses.
In rats, minimal azilsartan-associated radioactivity crossed the blood-brain barrier. Azilsartan passed across the placental barrier in pregnant rats and was distributed to the fetus.
Chlorthalidone: In whole blood, chlorthalidone is predominantly bound to erythrocyte carbonic anhydrase. In the plasma, approximately 75% of chlorthalidone is bound to plasma proteins, 58% of the drug being bound to albumin.
Metabolism and Elimination: Azilsartan Medoxomil: Azilsartan is metabolized to  two primary metabolites. The major metabolite in plasma is formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation, referred to as metabolite M-I. Systemic exposures to the major and minor metabolites in humans were approximately 50% and less than 1% of azilsartan, respectively. M-I and M-II do not contribute to the pharmacologic activity of azilsartan medoxomil. The major enzyme responsible for azilsartan metabolism is CYP2C9.
Following an oral dose of 14C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine, with 15% of the dose excreted in urine as azilsartan. The elimination half-life of azilsartan is approximately 11 hours and renal clearance is approximately 2.3 mL/min. Steady-state levels of azilsartan are achieved within 5 days and no accumulation in plasma occurs with repeated once-daily dosing.
Chlorthalidone: The major portion of the drug is excreted unchanged by the kidneys. Nonrenal routes of elimination have yet to be clarified. Data are not available regarding percentage of dose as unchanged drug and metabolites, concentration of the drug in body fluids, degree of uptake by a particular organ or in the fetus or passage across the blood-brain barrier.
Special Populations: Azilsartan Medoxomil: The effect of demographic and functional factors on the pharmacokinetics of azilsartan was studied in single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of the effect on azilsartan are presented in Figure 2 as change relative to reference (test/reference). (See Figure 2.)

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Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of azilsartan medoxomil and chlorthalidone. However, these studies have been conducted for azilsartan medoxomil alone.
Azilsartan Medoxomil: Carcinogenesis: Azilsartan medoxomil was not carcinogenic when assessed in 26-week transgenic (Tg.rasH2) mouse and 2-year rat studies. The highest doses tested (azilsartan medoxomil 450 mg/kg/day in the mouse and azilsartan medoxomil 600 mg/kg/day in the rat) produced exposures to azilsartan that are 12 (mice) and 27 (rats) times the average exposure to azilsartan in humans given the maximum recommended human dose (MRHD, azilsartan medoxomil 80 mg/day). M-II was not carcinogenic when assessed in 26-week Tg.rasH2 mouse and 2-year rat studies. The highest doses tested [approximately 8,000 mg M-II/kg/day (males) and 11,000 mg M-II/kg/day (females) in the mouse and 1,000 mg M-II/kg/day (males) and up to 3,000 mg M-II/kg/day (females) in the rat] produced exposures that are, on average, about 30 (mice) and 7 (rats) times the average exposure to M-II in humans at the MRHD.
Mutagenesis: Azilsartan medoxomil, azilsartan and M-II were positive for structural aberrations in the Chinese Hamster Lung Cytogenic Assay. In this assay, structural chromosomal aberrations were observed with the prodrug, azilsartan medoxomil, without metabolic activation. The active moiety, azilsartan, was also positive in this assay both with and without metabolic activation. The major human metabolite, M-II was also positive in this assay during a 24-hr assay without metabolic activation.
Azilsartan medoxomil, azilsartan and M-II were devoid of genotoxic potential in the Ames reverse mutation assay with Salmonella typhimurium and Escherichia coli, the in vitro Chinese Hamster Ovary Cell forward mutation assay, the in vitro mouse lymphoma (tk) gene mutation test, the ex vivo unscheduled DNA synthesis test, and the in vivo mouse and/or rat bone marrow micronucleus assay.
Impairment of Fertility: There was no effect of azilsartan medoxomil on the fertility of male or female rats at oral doses of up to azilsartan medoxomil 1,000 mg/kg/day [6,000 mg/m2 (approximately 122 times the MRHD of azilsartan medoxomil 80 mg/60 kg on a mg/m2 basis)]. Fertility of rats also was unaffected at doses of up to 3,000 mg M-II/kg/day.
Animal Toxicology and/or Pharmacology: Edarbyclor: The safety profiles of azilsartan medoxomil and chlorthalidone monotherapy have been individually established. To characterize the toxicological profile for Edarbyclor, a 13-week repeat-dose toxicity study was conducted in rats. The results of this study indicated that the combined administration of azilsartan medoxomil, M-II, and chlorthalidone resulted in increased exposures to chlorthalidone.
Pharmacologically-mediated toxicity, including suppression of body weight gain and decreased food consumption in male rats, and increases in blood urea nitrogen in both sexes, was enhanced by co-administration of azilsartan medoxomil, M-II, and chlorthalidone. With the exception of these findings, there were no toxicologically synergistic effects in this study.
In an embryofetal developmental study in rats, there was no teratogenicity or increase in fetal mortality in the litters of dams receiving azilsartan medoxomil, M-II and chlorthalidone concomitantly at maternally toxic doses.
Azilsartan Medoxomil: Reproductive Toxicology: In peri- and postnatal rat development studies, adverse effects on pup viability, delayed incisor eruption and dilatation of the renal pelvis along with hydronephrosis were seen when azilsartan medoxomil was administered to pregnant and nursing rats at 1.2 times the MRHD on a mg/m2 basis. Reproductive toxicity studies indicated that azilsartan medoxomil was not teratogenic when administered at oral doses up to 1,000 mg azilsartan medoxomil/kg/day to pregnant rats (122 times the MRHD on a mg/m2 basis) or up to 50 mg azilsartan medoxomil/kg/day to pregnant rabbits (12 times the MRHD on a mg/m2 basis). M-II also was not teratogenic in rats or rabbits at doses up to 3,000 mg M-II/kg/day. Azilsartan crossed the placenta and was found in the fetuses of pregnant rats and was excreted into the milk of lactating rats.
Chlorthalidone: Reproductive Toxicology: Reproduction studies have been performed in the rat and the rabbit at doses up to 420 times the human dose and have revealed no evidence of harm to the fetus. Thiazides cross the placental barrier and appear in cord blood.
Pharmacology: Biochemical studies in animals have suggested reasons for the prolonged effect of chlorthalidone. Absorption from the gastrointestinal tract is slow because of its low solubility. After passage to the liver, some of the drug enters the general circulation, while some is excreted in the bile, to be reabsorbed later. In the general circulation, it is distributed widely to the tissue, but is taken up in highest concentrations by the kidneys, where amounts have been found 72 hrs after ingestion, long after it has disappeared from other tissues. The drug is excreted unchanged in the urine.
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