CLINICAL PHARMACOLOGY
Mechanism of Action
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.
Pharmacokinetics
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 AVAPRO (irbesartan), peak plasma concentrations
of irbesartan are attained at 1.5–2 hours after dosing.
Food does not affect the bioavailability of AVAPRO.
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.
Metabolism and Elimination
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.
Distribution
Irbesartan is 90% bound to serum proteins (primarily
albumin and a 1-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.
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 C max 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 DRUG INTERACTIONS)
Pharmacodynamics
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.
Clinical Studies
The antihypertensive effects of AVAPRO (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 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 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 and 300 mg provided statistically and clinically
significant decreases in systolic and diastolic blood pressure
with trough (24 hours 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.
Once-daily administration of therapeutic doses of irbesartan
gave peak effects at around 3–6 hours and in one 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.
In controlled trials, the addition of irbesartan to hydrochlorothiazide
doses of 6.25, 12.5, or 25 mg produced further dose-related
reductions in blood pressure similar to those achieved with
the same monotherapy dose of irbesartan. HCTZ also had an
approximately additive effect.
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).
The effect of irbesartan is apparent after the first dose
and it is close to its full observed effect at 2 weeks.
At the end of an 8-week exposure, about 2/3 of the antihypertensive
effect was still present one 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.
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