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 primary vasoactive hormone of the
renin-angiotensin system, and an important component in the pathophysiology of
hypertension. It also stimulates aldosterone secretion by the adrenal cortex.
Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of
angiotensin II by selectively binding to the AT1 angiotensin II receptor found
in many tissues (e.g., vascular smooth muscle, adrenal gland). There is also an
AT2 receptor in many tissues, but it is not involved in cardiovascular
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.
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- to
2-fold rise in angiotensin II plasma concentration and a 2- to 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
The oral absorption of irbesartan is rapid and complete
with an average absolute bioavailability of 60% to 80%. Following oral administration
of AVAPRO, peak plasma concentrations of irbesartan are attained at 1.5 to 2
hours after dosing. Food does not affect the bioavailability of irbesartan.
Irbesartan exhibits linear pharmacokinetics over the
therapeutic dose range.
Irbesartan is 90% bound to serum proteins (primarily
albumin and α -acid glycoprotein) with negligible binding to cellular
components of blood. The average volume of distribution is 53 to 93 liters.
Studies in animals indicate that radiolabeled irbesartan
weakly crosses the blood-brain barrier and placenta. Irbesartan is excreted in
the milk of lactating rats.
Total plasma and renal clearances are in the range of 157
to 176 mL/min and 3.0 to 3.5 mL/min, respectively. The terminal elimination
half-life of irbesartan averages 11 to 15 hours. Steady-state concentrations
are achieved within 3 days. Limited accumulation of irbesartan ( < 20%) is
observed in plasma upon repeated once-daily dosing and is not clinically
Irbesartan is an orally active agent that does not
require biotransformation into an active form. 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.
In vitro studies indicate irbesartan is oxidized
primarily by CYP2C9; metabolism by CYP3A4 is negligible.
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
No sex-related differences in pharmacokinetics are
observed in healthy elderly (age 65-80 years) or in healthy young (age 18-40
years) subjects. In studies of hypertensive patients, there is no sex
difference in half-life or accumulation, but somewhat higher plasma
concentrations of irbesartan are observed in females (11%-44%). No sex-related
dosage adjustment is necessary.
In elderly subjects (age 65-80 years), irbesartan
elimination half-life is not significantly altered, but AUC and Cmax values are
about 20% to 50% greater than those of young subjects (age 18-40 years). AUC
and Cmax values are about 20% to 50% greater than those of young subjects (age
18-40 years). No dosage adjustment is necessary in the elderly.
In healthy black subjects, irbesartan AUC values are
approximately 25% greater than whites; there is no difference in Cmax values.
The pharmacokinetics of irbesartan are 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 AND PRECAUTIONS and DOSAGE AND
The pharmacokinetics of irbesartan following repeated
oral administration are not significantly affected in patients with mild to
moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with
In vitro studies show significant inhibition of the
formation of oxidized irbesartan metabolites with the known cytochrome CYP2C9
substrates/inhibitors sulphenazole, tolbutamide and nifedipine. However, in clinical
studies the consequences of concomitant irbesartan on the pharmacodynamics of
warfarin were negligible. Based on in vitro data, no interaction would be
expected with drugs whose metabolism is dependent upon cytochrome P450
isoenzymes 1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4.
In separate studies of patients receiving maintenance
doses of warfarin, hydrochlorothiazide, or digoxin, irbesartan administration
for 7 days has no effect on the pharmacodynamics of warfarin (prothrombin time)
or pharmacokinetics of digoxin. The pharmacokinetics of irbesartan are not
affected by coadministration of nifedipine or hydrochlorothiazide.
Animal Toxicology And/Or Pharmacology
When pregnant rats were treated with irbesartan from Day
0 to Day 20 of gestation (oral doses of 50 mg/kg/day, 180 mg/kg/day, and 650
mg/kg/day), increased incidences of renal pelvic cavitation, hydroureter and/or
absence of renal papilla were observed in fetuses at dosages ≥ 50 mg/kg/day
(approximately equivalent to the maximum recommended human dose [MRHD], 300
mg/day, on a body surface area basis). Subcutaneous edema was observed in
fetuses at dosages ≥ 180 mg/kg/day (about 4 times the MRHD on a body
surface area basis). As these anomalies were not observed in rats in which irbesartan
exposure (oral doses of 50, 150, and 450 mg/kg/day) was limited to gestation
days 6 to 15, they appear to reflect late gestational effects of the drug. In
pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated with
maternal mortality and abortion. Surviving females receiving this dose (about
1.5 times the MRHD on a body surface area basis) had a slight increase in early
resorptions and a corresponding decrease in live fetuses. Irbesartan was found
to cross the placental barrier in rats and rabbits.
The antihypertensive effects of AVAPRO were examined in 7
placebo-controlled 8- to 12-week trials in patients with baseline diastolic
blood pressures of 95 to 110 mmHg. Doses of 1 to 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 sex, age, and race.
Two of the seven placebo-controlled trials identified above examined the
antihypertensive effects of irbesartan and hydrochlorothiazide in combination.
The 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 mg and 300 mg provided statistically
and clinically significant decreases in systolic and diastolic blood pressure
with trough (24 hours post-dose) effects after 6 to 12 weeks of treatment
compared to placebo, of about 8-10/5-6 mmHg 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.
Figures 1 and 2
Once-daily administration of therapeutic doses of
irbesartan gave peak effects at around 3 to 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% to 70%. In a continuous
ambulatory blood pressure monitoring study, oncedaily 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 mg, 12.5 mg, 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, sex, 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
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
Nephropathy In Type 2 Diabetic Patients
The Irbesartan Diabetic Nephropathy Trial (IDNT) was a
randomized, placebo- and active-controlled, double-blind, multicenter study
conducted worldwide in 1715 patients with type 2 diabetes, hypertension (SeSBP
> 135 mmHg or SeDBP > 85 mmHg), and nephropathy (serum creatinine 1.0 to
3.0 mg/dL in females or 1.2 to 3.0 mg/dL in males and proteinuria ≥ 900
mg/day). Patients were randomized to receive AVAPRO 75 mg, amlodipine 2.5 mg,
or matching placebo once-daily. Patients were titrated to a maintenance dose of
AVAPRO 300 mg, or amlodipine 10 mg, as tolerated. Additional antihypertensive agents
(excluding ACE inhibitors, angiotensin II receptor antagonists and calcium
channel blockers) were added as needed to achieve blood pressure goal
( ≤ 135/85 or 10 mmHg reduction in systolic blood pressure if higher than
160 mmHg) for patients in all groups.
The study population was 66.5% male, 72.9% below 65 years
of age, and 72% White (Asian/Pacific Islander 5.0%, Black 13.3%, Hispanic
4.8%). The mean baseline seated systolic and diastolic blood pressures were 159
mmHg and 87 mmHg, respectively. The patients entered the trial with a mean
serum creatinine of 1.7 mg/dL and mean proteinuria of 4144 mg/day.
The mean blood pressure achieved was 142/77 mmHg for
AVAPRO, 142/76 mmHg for amlodipine, and 145/79 mmHg for placebo. Overall, 83.0%
of patients received the target dose of irbesartan more than 50% of the time.
Patients were followed for a mean duration of 2.6 years.
The primary composite endpoint was the time to occurrence
of any one of the following events: doubling of baseline serum creatinine,
end-stage renal disease (ESRD; defined by serum creatinine ≥ 6 mg/dL,
dialysis, or renal transplantation), or death. Treatment with AVAPRO resulted
in a 20% risk reduction versus placebo (p=0.0234) (see Figure 3 and Table 1).
Treatment with AVAPRO also reduced the occurrence of sustained doubling of
serum creatinine as a separate endpoint (33%), but had no significant effect on
ESRD alone and no effect on overall mortality (see Table 1).
Figure 3: IDNT: Kaplan-Meier Estimates of Primary
Endpoint (Doubling of Serum Creatinine, End-Stage Renal Disease or All-Cause
The percentages of patients experiencing an event during
the course of the study can be seen in Table 1 below:
Table 1: IDNT: Components of Primary Composite
|Comparison With Placebo
||Comparison With Amlodipine
|Primary Composite Endpoint
|Breakdown of first occurring event contributing to primary endpoint
| 2x creatinine
|Incidence of total events over entire period of follow-up
| 2 x creatinine
The secondary endpoint of the study was a composite of
cardiovascular mortality and morbidity (myocardial infarction, hospitalization
for heart failure, stroke with permanent neurological deficit, amputation).
There were no statistically significant differences among treatment groups in
these endpoints. Compared with placebo, AVAPRO significantly reduced
proteinuria by about 27%, an effect that was evident within 3 months of
starting therapy. AVAPRO significantly reduced the rate of loss of renal
function (glomerular filtration rate), as measured by the reciprocal of the
serum creatinine concentration, by 18.2%.
Table 2 presents results for demographic subgroups.
Subgroup analyses are difficult to interpret, and it is not known whether these
observations represent true differences or chance effects. For the primary endpoint,
AVAPRO's favorable effects were seen in patients also taking other
antihypertensive medications (angiotensin II receptor antagonists,
angiotensin-converting-enzyme inhibitors, and calcium channel blockers were not
allowed), oral hypoglycemic agents, and lipid-lowering agents.
Table 2: IDNT: Primary Efficacy Outcome Within
|Comparison With Placebo
| < 65
| ≥ 65