CoAprovel Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Irbesartan is a specific insurmountable antagonist of angiotensin II receptors (AT1 subtype). Angiotensin II is an important component of the renin-angiotensin system and is involved in the pathophysiology of hypertension and in sodium homeostasis. Irbesartan does not require metabolic activation for its activity.
Irbesartan blocks the potent vasoconstrictor and aldosterone-secreting effects of angiotensin II by selective antagonism of the angiotensin II (AT1 subtype) receptors localized on vascular smooth muscle cells and in the adrenal cortex. It has no agonist activity at the AT1 receptor and a much greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2 receptor (a receptor that has not been shown to be associated with cardiovascular homeostasis). Irbesartan does not inhibit enzymes involved in the renin-angiotensin system (ie, renin, angiotensin converting enzyme [ACE]) or affect other hormone receptors or ion channels involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Irbesartan blockade of AT1 receptors interrupts the feedback loop within the renin-angiotensin system, resulting in increases in plasma renin levels and angiotensin II levels. However, the resultant increase in plasma renin and angiotensin II levels does not overcome the effects of irbesartan on reducing blood pressure. Aldosterone plasma concentrations decline following irbesartan administration, however, serum potassium levels are not significantly affected (mean increase of <0.1 mEq/L) at the recommended doses. Irbesartan has no notable effects on serum triglycerides, cholesterol or glucose concentrations. There is no effect on serum uric acid or urinary uric acid excretion.
Hydrochlorothiazide is a benzothiadiazine (thiazide) diuretic with diuretic, natriuretic and antihypertensive effects. The mechanism of antihypertensive effect of thiazide diuretics, such as hydrochlorothiazide is not fully known. Thiazides affect the renal tubular mechanism of electrolyte reabsorption, increasing excretion of sodium and chloride in approximately equivalent amounts.
Natriuresis causes a secondary loss of potassium and bicarbonate. Hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium. Coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics.
Clinical Efficacy/Clinical Studies: Based on data from placebo-controlled clinical trials, the following effects were noted.
The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide was apparent after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 6-8 weeks. In long-term follow up studies, the effect of irbesartan/hydrochlorothiazide was maintained for over one year.
The combination of hydrochlorothiazide and irbesartan produced dose related additive reductions in blood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to 300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resulted in further placebo corrected diastolic blood pressure reductions at trough (24 hours post dosing) of 6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in overall placebo subtracted systolic/diastolic reductions of up to 13.6/11.5 mm Hg. Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide showed systolic/diastolic mean placebo-adjusted blood pressure reductions at trough (24 hours post dosing) of 12.9/6.9 mm Hg. Peak effects occurred at 3-6 hours. When assessed by ambulatory blood pressure monitoring, COAPROVEL 150/12.5 mg once daily produced consistent reduction in blood pressure over the 24 hour period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. The observed trough-to-peak effects were at least 68% of the corresponding placebo-subtracted peak diastolic and peak systolic responses.
In a clinical trial with patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan to the hydrochlorothiazide produced mean systolic/diastolic reductions which were 11.1/7.2 mm Hg greater than hydrochlorothiazide alone. Blood pressure was lowered to about the same extent in both standing and supine positions. Orthostatic effects were infrequent, but may be expected to occur in patients who develop intercurrent sodium and/or volume-depletion.
The effectiveness of irbesartan/hydrochlorothiazide was not influenced by age, race, or gender. The overall antihypertensive response to the combination was similar for black and non-black patients.
After withdrawal of irbesartan, blood pressure gradually returned toward baseline. Rebound hypertension was not observed with irbesartan or hydrochlorothiazide.
With hydrochlorothiazide, onset of diuresis occurred in 2 hours, and peak effect occurred at about 4 hours, while the action persisted for approximately 6-12 hours.
Initial Therapy: Two clinical studies evaluated COAPROVEL as initial therapy. The first study was conducted in patients with a mean baseline blood pressure of 162/98 mm Hg (Moderate Hypertension) and compared the change from baseline in SeSBP at 8 weeks between the combination group (irbesartan and HCTZ 150 mg/12.5 mg) to irbesartan (150 mg) and to HCTZ (12.5 mg). These initial study regimens were increased at 2 weeks to COAPROVEL 300 mg/25 mg, irbesartan 300 mg, or to HCTZ 25 mg, respectively.
Mean reductions from baseline for SeDBP and SeSBP at trough were 14.6 mm Hg and 27.1 mm Hg for patients treated with COAPROVEL, 11.6 mm Hg and 22.1 mm Hg for patients treated with irbesartan, and 7.3 mm Hg and 15.7 mm Hg for patients treated with HCTZ at 8 weeks, respectively. For patients treated with COAPROVEL, the mean change from baseline in SeDBP was 3.0 mm Hg lower (p=0.0013) and the mean change from baseline in SeSBP was 5.0 mm Hg lower (p=0.0016) compared to patients treated with irbesartan, and 7.4 mm Hg lower (p<0.0001) and 11.3 mm Hg lower (p<0.0001) compared to patients treated with HCTZ, respectively.
The second clinical study was conducted in patients with a mean baseline blood pressure of 172/113 mm Hg (Severe Hypertension) and compared trough SeDBP at 5 weeks between the combination group (irbesartan and HCTZ 150 mg/12.5 mg) and irbesartan (150 mg). These initial study regimens were increased at 1 week to COAPROVEL 300 mg/25 mg or to irbesartan 300 mg, respectively.
At 5 weeks, mean reductions from baseline for SeDBP and SeSBP at trough were 24.0 mm Hg and 30.8 mm Hg for patients treated with COAPROVEL and 19.3 mm Hg and 21.1 mm Hg for patients treated with irbesartan, respectively. The mean SeDBP was 4.7 mm Hg lower (p<0.0001) and the mean SeSBP was 9.7 mm Hg lower (p<0.0001) in the group treated with COAPROVEL than in the group treated with irbesartan. Patients treated with COAPROVEL achieved more rapid blood pressure control with significantly lower SeDBP and SeSBP and greater blood pressure control at every assessment (Week 1, Week 3, Week 5, and Week 7). Maximum effects were seen at Week 7.
The effectiveness of irbesartan/hydrochlorothiazide was not influenced by age, race, or gender. The overall antihypertensive response to the combination was similar for black and non-black patients.
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg).
Pharmacokinetics: Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the pharmacokinetics of irbesartan.
Absorption: Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for their activity. Following oral administration of COAPROVEL, the absolute oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the bioavailability of CoAprovel. Peak plasma concentration occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.
Distribution: Irbesartan is approximately 96% protein-bound in the plasma, and has negligible binding to cellular components of blood. The volume of distribution is 53-93 Liters (0.72-1.24 Liters/Kg). Hydrochlorothiazide is 68% protein-bound in the plasma, and its apparent volume of distribution is 3.6-7.8 Liters/Kg.
Metabolism: In plasma, unchanged irbesartan accounts for 80-85% of the circulating radioactivity following oral or intravenous administration of 14C irbesartan. Irbesartan is metabolized by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (~6%). Irbesartan undergoes oxidation primarily by the cytochrome P450 isoenzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. It is not metabolized by, nor does it substantially induce or inhibit most isoenzymes commonly associated with drug metabolism (ie, CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1). Irbesartan does not induce nor inhibit isoenzyme CYP3A4.
Elimination: Irbesartan and its metabolites are excreted by both biliary and renal routes. About 20% of the administered radioactivity after an oral or intravenous dose of 14C irbesartan is recovered in urine with the remainder in the feces. Less than 2% of the dose is excreted in urine as unchanged irbesartan. Hydrochlorothiazide is not metabolized and is eliminated by the kidneys. The mean plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours.
The terminal elimination half-life (t½) of irbesartan is 11-15 hours. The total body clearance of intravenously administered irbesartan is 157-176 mL/ min, of which 3.0-3.5 mL/min is renal clearance. Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range. Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation (<20%) is observed in plasma upon repeated once-daily dosing.
Special Populations: Gender: In male and female hypertensive subjects, higher (11-44%) plasma concentrations of irbesartan were observed in females than in males, although, following multiple dosing, males and females did not show differences in either accumulation or elimination half-life. No gender-specific differences in clinical effect have been observed.
Elderly Patients: In elderly (male and female) normotensive subjects (65-80 years) with clinically normal renal and hepatic function, the plasma AUC and peak plasma concentrations (Cmax) of irbesartan are approximately 20%-50% greater than those observed in younger subjects (18-40 years). Regardless of age, the elimination half-life is comparable. No significant age-related differences in clinical effect have been observed. The area under the plasma concentration time curve (AUC) for hydrochlorothiazide was elevated in the elderly group following multiple dosing consistent with previously published data.
Hepatic Impairment: In patients with hepatic insufficiency due to mild to moderate cirrhosis, the pharmacokinetics of irbesartan are not significantly altered.
Renal Impairment: In patients with renal impairment (regardless of degree) and in hemodialysis patients, the pharmacokinetics of irbesartan are not significantly altered. Irbesartan is not removed by hemodialysis. In patients with severe renal impairment (creatinine clearance <20 mL/min), the elimination half-life of hydrochlorothiazide was reported to increase to 21 hours.
Race: In black and white normotensive subjects, the plasma AUC and t½ of irbesartan are approximately 20-25% greater in blacks than in whites; the peak plasma concentrations (C_max) of irbesartan are essentially equivalent.