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 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 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.
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-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 uricosuric effect.
Pharmacokinetics
Absorption
The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60%
to 80%. Following oral administration of irbesartan tablets, 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.
Distribution
Irbesartan is 90% bound to serum proteins (primarily albumin and α1-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.
Elimination
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 relevant.
Metabolism
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.
Excretion
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.
Specific Populations
Sex
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.
Geriatrics
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).
No dosage adjustment is necessary in the elderly.
Race/Ethnicity
In healthy black subjects, irbesartan AUC values are approximately 25% greater than whites; there is no
difference in Cmax values.
Renal Impairment
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 ADMINISTRATION].
Hepatic Insufficiency
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 hepatic insufficiency.
Drug-Drug Interactions
In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the
known cytochrome CYP 2C9 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 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.
Clinical Studies
Hypertension
The antihypertensive effects of irbesartan tablets 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 mg 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 (1mg
to 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.
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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 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.
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
irbesartan 75 mg, amlodipine 2.5 mg, or matching placebo once-daily. Patients were titrated to a
maintenance dose of irbesartan 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 irbesartan, 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 irbesartan tablets resulted in a 20%
risk reduction versus placebo (p=0.0234) (see Figure 3 and Table 1). Treatment with irbesartan tablets
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).
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 Endpoint
|
IRBESARTAN
TABLETS
N=579
(%) |
Comparison With Placebo |
Comparis on With
Amlodipine |
Placebo
N=569 (%) |
Hazard
Ratio |
95% CI |
Amlodipine
N=567 (%) |
Hazard
Ratio |
95%
CI |
Primary
Composite
Endpoint |
32.6 |
39.0 |
0.80 |
0.66-0.97
(p=0.0234) |
41.1 |
0.77 |
0.63-
0.93 |
Breakdown of first occurring event contributing to primary endpoint |
2x creatinine |
14.2 |
19.5 |
- |
- |
22.8 |
- |
- |
ESRD |
7.4 |
8.3 |
- |
- |
8.8 |
- |
- |
Death |
11.1 |
11.2 |
- |
- |
9.5 |
- |
- |
Incidence of total events over entire period of follow-up |
2x creatinine |
16.9 |
23.7 |
0.67 |
0.52-0.87 |
25.4 |
0.63 |
0.49-
0.81 |
ESRD |
14.2 |
17.8 |
0.77 |
0.57-1.03 |
18.3 |
0.77 |
0.57-
1.03 |
Death |
15.0 |
16.3 |
0.92 |
0.69-1.23 |
14.6 |
1.04 |
0.77-
1.40 |
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, irbesartan tablets significantly reduced proteinuria by about 27%, an
effect that was evident within 3 months of starting therapy. Irbesartan tablets 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, irbesartan tablets 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 Subgroups
Baseline Factors |
Irbesartan tablets N=579 (%) |
Comparison With Placebo |
Placebo N=569 (%) |
Hazard Ratio |
95% Cl |
Sex |
Male |
27.5 |
36.7 |
0.68 |
0.53-0.88 |
Female |
42.3 |
44.6 |
0.98 |
0.72-1.34 |
Race |
White |
29.5 |
37.3 |
0.75 |
0.60-0.95 |
Non-White |
42.6 |
43.5 |
0.95 |
0.67-1.34 |
Age (years) |
<65 |
31.8 |
39.9 |
0.77 |
0.62-0.97 |
≥65 |
35.1 |
36.8 |
0.88 |
0.61-1.29 |