CLINICAL PHARMACOLOGY
Mechanism of Action
Irbesartan
Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system (RAS) and also stimulates aldosterone synthesis and secretion by adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth. Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT1 angiotensin II receptor. There is also an AT2 receptor in many tissues, but it is not involved in cardiovascular homeostasis.
Irbesartan is a specific competitive antagonist of AT1 receptors with a much greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2 receptor, and no agonist activity.
Blockade of the AT1 receptor removes the negative feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II do not overcome the effects of irbesartan on blood pressure.
Irbesartan does not inhibit ACE or renin or affect other hormone receptors or ion channels known to be involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Because irbesartan does not inhibit ACE, it does not affect the response to bradykinin; whether this has clinical relevance is not known.
Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is not fully understood.
Pharmacokinetics
Irbesartan
Irbesartan is an orally active agent that does not require biotransformation into an active form. The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60–80%. Following oral administration of irbesartan, peak plasma concentrations of irbesartan are attained at 1.5–2 hours after dosing. Food does not affect the bioavailability of irbesartan.
Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range.
The terminal elimination half-life of irbesartan averaged 11–15 hours. Steady-state concentrations are achieved within 3 days. Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing.
Hydrochlorothiazide
When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.
Metabolism and Elimination
Irbesartan
Irbesartan is metabolized via glucuronide conjugation and oxidation. Following oral or intravenous administration of 14C-labeled irbesartan, more than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan. The primary circulating metabolite is the inactive irbesartan glucuronide conjugate (approximately 6%). The remaining oxidative metabolites do not add appreciably to irbesartan’s pharmacologic activity.
Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either oral or intravenous administration of 14C-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide.
In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes indicated irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was negligible. Irbesartan was neither metabolized by, nor did it substantially induce or inhibit, isoenzymes commonly associated with drug metabolism (1A1, 1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition of 3A4.
Hydrochlorothiazide
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.
Distribution
Irbesartan
Irbesartan is 90% bound to serum proteins (primarily albumin andα1-acid glycoprotein) with negligible binding to cellular components of blood. The average volume of distribution is 53–93 liters. Total plasma and renal clearances are in the range of 157–176 and 3.0–3.5 mL/min, respectively. With repetitive dosing, irbesartan accumulates to no clinically relevant extent.
Studies in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain barrier and placenta. Irbesartan is excreted in the milk of lactating rats.
Hydrochlorothiazide
Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Special Populations
Pediatric
Irbesartan-hydrochlorothiazide pharmacokinetics have not been investigated in patients <18 years of age.
Gender
No gender related differences in pharmacokinetics were observed in healthy elderly (age 65–80 years) or in healthy young (age 18–40 years) subjects. In studies of hypertensive patients, there was no gender difference in half-life or accumulation, but somewhat higher plasma concentrations of irbesartan were observed in females (11–44%). No gender-related dosage adjustment is necessary.
Geriatric
In elderly subjects (age 65–80 years), irbesartan elimination half-life was not significantly altered, but AUC and Cmax values were about 20–50% greater than those of young subjects (age 18–40 years). No dosage adjustment is necessary in the elderly.
Race
In healthy black subjects, irbesartan AUC values were approximately 25% greater than whites; there were no differences in Cmax values.
Renal Insufficiency
The pharmacokinetics of irbesartan were not altered in patients with renal impairment or in patients on hemodialysis. Irbesartan is not removed by hemodialysis. No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also volume depleted. (See WARNINGS: Hypotension in Volume- or Salt-depleted Patients and DOSAGE AND ADMINISTRATION.)
Hepatic Insufficiency
The pharmacokinetics of irbesartan following repeated oral administration were not significantly affected in patients with mild to moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.
Drug Interactions
(See PRECAUTIONS: Drug Interactions.)
Pharmacodynamics
Irbesartan
In healthy subjects, single oral irbesartan doses of up to 300 mg produced dose-dependent inhibition of the pressor effect of angiotensin II infusions. Inhibition was complete (100%) 4 hours following oral doses of 150 mg or 300 mg and partial inhibition was sustained for 24 hours (60% and 40% at 300 mg and 150 mg, respectively).
In hypertensive patients, angiotensin II receptor inhibition following chronic administration of irbesartan causes a 1.5–2 fold rise in angiotensin II plasma concentration and a 2–3 fold increase in plasma renin levels. Aldosterone plasma concentrations generally decline following irbesartan administration, but serum potassium levels are not significantly affected at recommended doses.
In hypertensive patients, chronic oral doses of irbesartan (up to 300 mg) had no effect on glomerular filtration rate, renal plasma flow or filtration fraction. In multiple dose studies in hypertensive patients, there were no clinically important effects on fasting triglycerides, total cholesterol, HDL-cholesterol, or fasting glucose concentrations. There was no effect on serum uric acid during chronic oral administration and no uricosuric effect.
Hydrochlorothiazide
After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Clinical Studies
Irbesartan
The antihypertensive effects of irbesartan were examined in seven (7) major placebo-controlled, 8–12 week trials in patients with baseline diastolic blood pressures of 95–110 mmHg. Doses of 1–900 mg were included in these trials in order to fully explore the dose-range of irbesartan. These studies allowed a comparison of once- or twice-daily regimens at 150 mg/day, comparisons of peak and trough effects, and comparisons of response by gender, age, and race. Two of the seven placebo-controlled trials identified above and two additional placebo-controlled studies examined the antihypertensive effects of irbesartan and hydrochlorothiazide in combination.
The seven (7) studies of irbesartan monotherapy included a total of 1915 patients randomized to irbesartan (1–900 mg) and 611 patients randomized to placebo. Once-daily doses of 150 to 300 mg provided statistically and clinically significant decreases in systolic and diastolic blood pressure with trough (24 hour post-dose) effects after 6–12 weeks of treatment compared to placebo, of about 8–10/5–6 and 8–12/5–8 mmHg, respectively. No further increase in effect was seen at dosages greater than 300 mg. The dose-response relationships for effects on systolic and diastolic pressure are shown in Figures 1 and 2.
Once-daily administration of therapeutic doses of irbesartan gave peak effects at around 3–6 hours and, in one continuous ambulatory blood pressure monitoring study, again around 14 hours. This was seen with both once-daily and twice-daily dosing. Trough-to-peak ratios for systolic and diastolic response were generally between 60–70%. In a continuous ambulatory blood pressure monitoring study, once-daily dosing with 150 mg gave trough and mean 24-hour responses similar to those observed in patients receiving twice-daily dosing at the same total daily dose.
Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over and under 65 years of age, had generally similar responses. Irbesartan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in blacks (usually a low-renin population). Black patients typically show an improved response with the addition of a low dose diuretic (e.g., 12.5 mg hydrochlorothiazide).
The effect of irbesartan is apparent after the first dose and is close to the full observed effect at 2 weeks. At the end of the 8-week exposure, about 2/3 of the antihypertensive effect was still present 1 week after the last dose. Rebound hypertension was not observed. There was essentially no change in average heart rate in irbesartan-treated patients in controlled trials.
Irbesartan-Hydrochlorothiazide
The antihypertensive effects of AVALIDE (irbesartan-hydrochlorothiazide) Tablets were examined in 4 placebo-controlled studies of 8–12 weeks in patients with mild-moderate hypertension. These trials included 1914 patients randomized to fixed doses of irbesartan (37.5 to 300 mg) and concomitant hydrochlorothiazide (6.25 to 25 mg). One factorial study compared all combinations of irbesartan (37.5, 100, and 300 mg or placebo) and hydrochlorothiazide (6.25, 12.5, and 25 mg or placebo). The irbesartan-hydrochlorothiazide combinations of 75/12.5 mg and 150/12.5 mg were compared to their individual components and placebo in a separate study. A third study investigated the ambulatory blood pressure responses to irbesartan-hydrochlorothiazide (75/12.5 mg and 150/12.5 mg) and placebo after 8 weeks of dosing. Another trial investigated the effects of the addition of irbesartan (75 mg) in patients not controlled on hydrochlorothiazide (25 mg) alone.
In controlled trials, the addition of irbesartan 150–300 mg to hydrochlorothiazide doses of 6.25, 12.5, or 25 mg produced further dose-related reductions in blood pressure of 8–10/3–6 mmHg, comparable to those achieved with the same monotherapy dose of irbesartan. The addition of hydrochlorothiazide to irbesartan produced further dose-related reductions in blood pressure at trough (24 hours post-dose) of 5–6/2–3 mmHg (12.5 mg) and 7–11/4–5 mmHg (25 mg), also comparable to effects achieved with hydrochlorothiazide alone. Once-daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide, 300 mg irbesartan and 12.5 mg hydrochlorothiazide, or 300 mg irbesartan and 25 mg hydrochlorothiazide produced mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of about 13–15/7–9, 14/9–12, and 19–21/11–12 mmHg, respectively. Peak effects occurred at 3–6 hours, with the trough-to-peak ratios >65%.
In another study, irbesartan (75–150 mg) or placebo was added on a background of 25 mg hydrochlorothiazide in patients not adequately controlled (SeDBP 93–120 mmHg) on hydrochlorothiazide (25 mg) alone. The addition of irbesartan (75–150 mg) gave an additive effect (systolic/diastolic) at trough (24 hours post-dosing) of 11/7 mmHg.
There was no difference in response for men and women or in patients over or under 65 years of age. Black patients had a larger response to hydrochlorothiazide than non-black patients and a smaller response to irbesartan. The overall response to the combination was similar for black and non-black patients.
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