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 sys-tem, 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 re-absorption,
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.
*Registered trademark of Sanofi-Synthelabo, Inc.
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 percent of the oral dose
is eliminated unchanged within 24 hours.
Distribution
Irbesartan
Irbesartan is 90% bound to serum proteins (primarily
albumin and a1-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 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.
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,
and 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 irbe-sartan (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, com-parable 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 irbesar-tan 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 hydrochloroth-iazide (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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