Expert Opinion on Investigational Drugs

Johnston
Irbesartan: a pharmacologic and clinical review
Monthly Focus: Cardiovascular & Renal

Pharmacology of irbesartan
Colin I Johnston
University of Melbourne, Department of Medicine, Austin Campus,
Heidelberg 3084, Victoria, Australia
http://www.ashley-pub.com
Despite the introduction of new antihypertensive agents such as
angiotensin-converting enzyme inhibitors and calcium channel antago-
Drug Evaluation nists, the blood pressure of fewer than 30% of hypertensive patients is
1. Overview of the market controlled with current therapies; compliance and continuation with
medication are poor. The renin-angiotensin system is important in the
2. Angiotensin II receptor pathophysiology of hypertension, end-organ damage and congestive
antagonists (AIIRAs) cardiac failure. Irbesartan is an angiotensin II receptor antagonist that
3. Introduction to irbesartan provides dose-dependent, specific, insurmountable blockade of the AT1
receptor both in vivo and in vitro. It is rapidly absorbed after oral admini-
4. Pharmacodynamics stration, has a bioavailability of 60 - 80% with no food effect, does not
5. Pharmacokinetics and require metabolism to a bioactive compound, and is excreted by both
metabolism biliary and renal routes so that dosage adjustments are unnecessary in
patients with renal or hepatic disease. Irbesartan produces dose-dependent
6. Clinical efficacy blood pressure reductions, with 24 h activity confirmed by ambulatory
7. Safety and tolerability blood pressure monitoring. Irbesartan is effective in the elderly and
non-elderly, men and women and in cases of mild and severe hypertension.
8. Regulatory affairs The recommended starting dosage is 150 mg once daily (o.d.), which can
be increased to 300 mg. Its antihypertensive effect is accentuated by
9. Clinical role and future
diuretic co-administration. In controlled clinical trials, irbesartan was at
studies
least as effective as atenolol, hydrochlorothiazide, amlodipine and
10. Conclusions enalapril. In a double-blind study, irbesartan 300 mg was more effective
than losartan 100 mg, and in a dose-titration study, irbesartan 150 - 300 mg
Acknowlegements
produced significantly greater blood pressure reductions than losartan 50 -
Bibliography 100 mg. In pooled data from nine placebo-controlled studies, adverse event
and discontinuation rates for irbesartan were similar to those for placebo,
and there was no relationship between dose and adverse effects. Prelimi-
nary clinical data suggest positive haemodynamic effects in heart failure
and renoprotective effects in diabetic nephropathy.
Keywords: angiotensin II receptor antagonists, clinical, hypertension,
irbesartan, preclinical

Exp. Opin. Invest. Drugs (1999) 8(5):655-670

1. Overview of the market

1.1 Unmet needs of currently available therapies
Hypertension continues to represent an important risk factor for morbidity
and mortality, producing a significant disease burden worldwide. In fact,
hypertension was the third leading risk factor for death and disability
reported in an international study, following malnutrition and tobacco use
[1]. In the United States, studies show that only approximately one half of all
hypertensive individuals are being treated [2,3]. Critical to the morbidity and
mortality associated with hypertension is the fact that less than one quarter
655
1999 © Ashley Publications Ltd. ISSN 1354-3784
656 Irbesartan: a pharmacologic and clinical review
Figure 1: Antihypertensive therapy continuation rates at 1 year [6].
35
30
25
% Continued
at one year
20
15
10
0
ACE
inhibitor
(n = 273)
of the total hypertensive population is considered to
be adequately controlled (defined as a blood pressure
less than 140/90 mm Hg) on currently available
medications [2,3].
The overall effectiveness of antihypertensive therapy
is impacted not only by the efficacy of the agent as
demonstrated in controlled clinical trials, but also by
its pharmacokinetic profile, pharmacodynamic
properties, safety and side-effect profile. It has been
postulated that pharmacokinetic and pharmacody-
namic differences between agents of different classes,
or among members of the same class of agent may
have resulting clinical implications [4]. Differentiating
features may include mechanism of action, absorp-
tion, biotransformation, protein binding, and/or
linearity of plasma concentrations with dose. In
addition, each drug class is associated with a unique
side-effect profile, which can limit treatment and
affect patient compliance, and hence, reduce overall
effectiveness [5]. In one study, almost 90% of patients
who were prescribed antihypertensive drug therapy
discontinued the therapy during the first year [6]. The
percentages of patients continuing therapy differed
among the classes of antihypertensive agents, with the
angiotensin-converting enzyme (ACE) inhibitors
having the highest continuation rate (33%) and
diuretics having the lowest (5%) at one year (Figure
1) [6]. Another study that examined antihypertensive
drug choice as a determinant of patient compliance
also showed that the likelihood of discontinuing
therapy was related to the choice of initial prescribed
agent [7]. Similar to the above results [6], ACE
© Ashley Publications Ltd. All rights reserved.
Calcium Beta Diuretic
channel blocker blocker (n = 2921)
(n = 1070) (n = 1356)
Prescribed antihypertensive medication
inhibitors had the highest compliance rate and
diuretics the lowest at five years.
The development of an effective and better-tolerated
therapy would have the potential to improve patient
compliance and hence overall effectiveness in
controlling blood pressure, thus satisfying an existing
unmet need in hypertension.
1.2Competitor compounds in clinic and late
development
The most recent additions to the antihypertensive
group of agents have been those that reduce blood
pressure through interaction with the renin-
angiotensin system (RAS). This system plays a pivotal
role in blood pressure regulation and in the develop-
ment of hypertension. The RAS consists of a cascade
of enzymatic reactions that act on angiotensinogen
and angiotensin I (AI), two precursors to angiotensin
II (AII). AII is a potent vasoconstrictor, and thus
blockade of its pressor effects by inhibition of its
synthesis or blockade of its receptor is the target of
various classes of antihypertensive agents (Figure 2).
1.2.1 Renin inhibitors
Renin inhibitors inhibit AII synthesis through
blockade of the formation of AI from angiotensino-
gen. Like the ACE inhibitors, a drawback with this
class of agents is that AII can be directly formed from
angiotensinogen through non-renin enzymes, such as
t-PA, cathepsin G and tonin. Also, low oral bioavail-
ability has limited the clinical usefulness of this class
of compounds.
Exp. Opin. Invest. Drugs (1999) 8(5)

Figure 2: The site of activity within the renin-angiotensin system of angiotensin converting enzyme (ACE) inhibitors and angiotensin
II (AII) receptor antagonists.
AT: Angiotensin; PGE: Prostoglandin E.
Non-ACE
Enzymes
AT2 receptors
1.2.2 ACE inhibitors
ACE inhibitors block the hydrolysis of AI to AII,
effectively inhibiting the formation of AII through this
enzymatic pathway. It is extensively documented that
ACE inhibitors reduce blood pressure as well as
reduce the risk of myocardial infarction and mortality
from congestive heart failure [8,9] and the risk of
ischaemic events [10]. However, the ACE enzyme also
metabolises many other substrates including bradyki-
nin to inactive kinin fragments, in addition to
catalysing the AI conversion. ACE inhibitors block the
degradation of bradykinin, and it is the accumulation
of this peptide and other tachykinins that is believed
to contribute to the development of cough, a common
side-effect of ACE inhibitors [11,12]. Correlated with
this tolerability issue is reduced patient compliance
that results from dissatisfaction with ACE inhibitors.
Another drawback with ACE inhibitors is their
inability to prevent AII synthesis through non-ACE
pathways, such as through chymostatin-sensitive
AII-generating enzyme- (CAGE), chymase-, and
cathepsin G-mediated reactions (Figure 2). Further-
more, ACE inhibitors are reversible competitive
inhibitors, and as the levels of plasma renin and
angiotensin increase, the reaction drives the
formation of angiotensin II, which is the explanation
for the return of plasma angiotensin II toward normal
levels during chronic ACE inhibitor therapy.
2. Angiotensin II receptor antagonists
(AIIRAs)
2.1 Mechanism of action
The AT1 subtype of AII receptors mediates all of the
known cardiovascular effects of AII, which include
© Ashley Publications Ltd. All rights reserved.
Johnston 657
Angiotensin I Bradykinin
Nitric oxide
PGE
ACE ACE
inhibitors
Angiotensin II Inactive
kinin
fragments
AII receptor
antagonists
AT1receptors
vasoconstriction, increased blood volume and cardiac
and vascular remodelling, each of which contribute to
increased blood pressure. In contrast, the role of the
AT2 receptor is believed to be in antiproliferation,
endothelial cell growth, and vasodilation. These
actions counteract those mediated by the AT 1
receptor, which may contribute to the balance
between cell proliferation and cell growth inhibition,
and between vasodilation and vasoconstriction.
The AIIRAs selectively block the AT1 subtype of AII
receptors. Unlike ACE inhibitors, AIIRAs modulate the
RAS through direct blockade of the AT1 receptor.
Blockade of angiotensin at the AT1 receptor should
result in a more specific and complete blockade of the
cardiovascular effects of AII. Moreover, since the
AIIRAs do not interfere with ACE or other enzyme
systems involved in the production of AII, they do not
potentiate bradykinin or other tachykinins. This may
translate into clinical benefits by improving
tolerability and patient compliance, thereby providing
better blood pressure control. It is also speculated that
the AIIRA class of agents may exert additional antipro-
liferative effects through AT2 receptor activation.
Stimulation of the unblocked AT2 receptor could
theoretically control cell proliferation or differentia-
tion, which would have potential clinical implications
in pathologic conditions such as left ventricular
hypertrophy and post-myocardial infarction.
2.2 AIIRAs marketed for clinical use
Losartan, valsartan, irbesartan, eprosartan, and
candesartan are AIIRAs that are currently marketed in
the United States and/or other countries worldwide
for the treatment of hypertension. Despite having
similar modes of action (i.e., selective blockade of the
AT 1 r eceptor), phar macokinetic and
Exp. Opin. Invest. Drugs (1999) 8(5)
658 Irbesartan: a pharmacologic and clinical review
Table 1: Pharmacokinetic/pharmacodynamic differentiating features [4].
Drug (active Bioavailability (%) Food effect
metabolite)
Losartan [EXP3174] 33 Minimal
Valsartan 25 > 40 - 50%
Candesartan 40 No
Irbesartan 60 - 80 No
Figure 3: Irbesartan is 2-butyl-3-[2′-(1H-tetrazol-5-
-yl)biphenyl-4-yl)methyl)]-1,3-diazospironon-1-en-4-one.
Irbesartan molecular weight = 428.5, melting point = 180°C -
181°C, octanol/water partition co-efficient at pH 7.4 = 10.8.
O
N
N (CH2)3CH3
N
N NH
N adrenal cortical membranes [14] and human vascular
pharmacodynamic differences exist among the
AIIRAs, which may have resulting clinical implications
(Table 1) [4]. As will be summarised in the following
sections, irbesartan possesses pharmacokinetic and
pharmacodynamic properties that may provide
clinical benefits over other agents within the same
class.
3. Introduction to irbesartan
Irbesartan (BMS-186295, SR 47436) was discovered by
Sanofi and developed jointly by Bristol-Myers Squibb
and Sanofi. Irbesartan is a nonpeptidic, substituted
biphenyl tetrazole (Figure 3), approximately 1.5
times more lipophilic than losartan, and more than
100 times more lipophilic than the active metabolite of
losartan, EXP 3174 [13]. As with the other AIIRAs,
irbesartan selectively blocks the AT1 receptor, thus
effectively blocking the cardiovascular effects of AII.
Irbesartan has been recently approved for clinical use
in the United States, Europe (United Kingdom,
Germany, Netherlands, Sweden, Ireland, France,
Greece, Italy, Spain, Switzerland, Norway, Austria and
Romania), Puerto Rico, Mexico, South Africa, Brazil,
© Ashley Publications Ltd. All rights reserved.
Half-life (h) Volume of Dosage (mg)
distribution (l)
2 [6-9] 34 [12] 50 - 100 given once
or twice per day
6 17 80 - 320 given once
per day
9 5 - 15 4 - 32 given once per
day
11 - 15 53 - 93 150 - 300 once per
day
Canada, Argentina, Australia and Chile. Irbesartan has
been administered in clinical trials to more than 8500
individuals, approximately 2000 of whom have been
treated for longer than one year.
4. Pharmacodynamics
4.1 Receptor binding
Irbesartan selectively blocks the AT1 subtype of AII
receptors in a dose-related manner, as demonstrated
in vitro in receptor binding assays using rat liver and
smooth muscle cells [15]. Irbesartan was 10,000-fold
more specific for the AT1 receptor than for the AT2
receptor. The affinity of irbesartan for the AT1 receptor
was ten-fold higher than that of losartan [14,15].
Irbesartan did not show activity on various other
receptors or ionic channels, or on renin and ACE.
4.2 Functional AII antagonism
Irbesartan produced dose-related antagonism of the
AII-induced contraction of rabbit aorta in vitro [16].
With increasing irbesartan concentrations, the
contractile response curve was shifted down and to
the right, without total recovery of the maximal
response, demonstrating insurmountable antagonism
(Figure 4). In vivo, irbesartan non-competitively
inhibited the AII pressor response in pithed rats [17].
This functional AII antagonism was also demonstrated
in clinical studies in normotensive subjects. Irbesartan
blocked the pressor response induced by exogenous
AII, which was maintained 24 h after dosing with
single oral doses of 25 - 300 mg [18,19]. At irbesartan
doses of 150 mg and 300 mg, blockade was approxi-
mately 100% within 2 - 4 h of dosing (Figure 5). After
24 h, these irbesartan doses maintained 45% and 60%
inhibition, respectively, in contrast to losartan, which
inhibited the response to AII by approximately 45% at
Exp. Opin. Invest. Drugs (1999) 8(5)
 Johnston 659
Figure 4: Dose-related inhibition of angiotensin II-induced contraction of rabbit aorta by irbesartan [16].

100

80
% Control

60 Irbesartan nM
0
40 1
3
20 10
30

0
-10 -9 -8 -7 -6
Angiotensin II (log M)

Figure 5: Inhibition of response to exogenous angiotensin II by irbesartan in normotensive subjects [4].

0 Irbesartan 75 mg
Irbesartan 150 mg
Irbesartan 300 mg
25

% 50
Inhibition

75

100
0 2
24 h with all doses tested (40 mg, 80 mg and 120 mg)
[4]. Furthermore, in a direct comparative trial in 18
healthy normotensive subjects, the starting dose of
irbesartan (150 mg) provided more complete and
more sustained blockade of exogenous AII than the
starting doses of losartan (50 mg) or valsartan (80 mg)
[20]. Irbesartan also increased plasma renin and
circulating AII levels in a dose-related manner
[18,19,21].
5. Pharmacokinetics and metabolism
5.1 Absorption and distribution
Irbesartan is rapidly and completely absorbed after
oral administration. Bioavailability is 60 - 80% [22],
which is unaffected by food [23]. Maximum plasma
concentrations are achieved within 1.5 - 2 h after
irbesartan administration, and the half-life is 11 - 15 h
[22,24]. Steady-state plasma concentrations are
achieved within three days of dosing and are linear
with dose over the therapeutic dose range. There is
© Ashley Publications Ltd. All rights reserved.
4 8 12 24
Time (h)
limited (< 20%) accumulation with repeated dosing
[4,24].
Irbesartan has a high volume of distribution, which
may allow it to reach AT1 receptors in tissue sites not
accessible to other AIIRAs [4,13].
5.2 Metabolism and excretion
Irbesartan does not require biotransformation to an
active metabolite for its pharmacologic activity [4,14].
It is metabolised in the liver by glucuronidation and
oxidation by the CYP2C9 system. Greater than 80% of
circulating radioactivity is due to unchanged
irbesartan [4]. Irbesartan is excreted by both the
hepatic and renal routes [4].
5.3 Pharmacokinetics in special populations
There were no clinically or statistically significant
differences in irbesartan pharmacokinetics in patients
with hepatic insufficiency [25,26], with renal insuffi-
ciency, or on haemodialysis [27]. Therefore, no
irbesartan dose adjustment is necessary for hepatically
Exp. Opin. Invest. Drugs (1999) 8(5)
660 Irbesartan: a pharmacologic and clinical review
Figure 6: Relationship between daily irbesartan (log) dose and reduction in trough seated diastolic blood pressure (SeDBP) [36].
8
7
6
5
Placebo-subtracted
reduction in trough
SeDBP (mm Hg)
-1
-2
0.1
or renally impaired patients based on pharmacoki-
netic considerations. Patients older than 65 years of
age had higher AUC and Cmax values and lower Tmax
values than those 65 years of age and younger;
however, these differences were clinically insignifi-
cant. There were also no differences in irbesartan
pharmacokinetics between men and women [4,28,29].
5.4 Drug interactions
The pharmacokinetics of irbesartan were not signifi-
cantly alter ed by nifedipine [30,31],
hydrochlorothiazide (HCTZ) [32], tolbutamide, or
antacids [data on file, Bristol-Myers Squibb/Sanofi].
Irbesartan did not affect the pharmacokinetics of
digoxin [4] or the pharmacodynamics or pharmacoki-
netics of warfarin [4,33].
6. Clinical efficacy
6.1 Phase I studies
As discussed in Section 4.2, in Phase I studies of
normotensive subjects, irbesartan produced a
dose-related inhibition of the pressor response to AII,
which was maintained for at least 24 h after dosing
[4,18,19,21]. Plasma AII and renin levels, indirect
indicators of pharmacologic blockade in the RAS,
were also elevated following irbesartan administra-
tion to healthy subjects [18,19,21].
© Ashley Publications Ltd. All rights reserved.
Estimated difference from placebo (±SE)
Model
1 10 100 1000
Dose of irbesartan (mg/day)
6.2 Phase II studies
Two double-blind, placebo-controlled, dose-ranging
studies were conducted in patients with mild-to-
moderate hypertension (seated diastolic blood
pressure [SeDBP] 95 - 110 mm Hg) to assess the
relationship between irbesartan dose and blood
pressure lowering [34]. The combined results of these
two studies (n = 889) showed that irbesartan
produced a dose-related reduction in blood pressure,
with statistically significant reductions over placebo at
dosages of 50 - 300 mg o.d. at week 8. Plasma
irbesartan concentrations were linear with dose, and
AII and aldosterone levels also showed dose-related
changes.
6.3 Phase III studies
6.3.1 Double-blind, placebo-controlled studies
A third double-blind, randomised, placebo-controlled
study demonstrated dose-related antihypertensive
effects of irbesartan in patients with mild-to-moderate
hypertension [35]. Patients received one of two
dose-titrated irbesartan regimens (irbesartan initiated
at 75 mg o.d. (n = 104) or irbesartan initiated at 150 mg
(n = 98)) or placebo (n = 117) for 12 weeks. After six
weeks, the doses were doubled for patients whose
blood pressure had not normalised (SeDBP ≥ 90 mm
Hg), to 150 mg and 300 mg, respectively. Both
regimens produced significant reductions in blood
pressure compared with placebo (p < 0.01 for each
Exp. Opin. Invest. Drugs (1999) 8(5)

Figure 7: Effects of irbesartan on ambulatory systolic and diastolic blood pressure (ASBP, ADBP) over 24 h (irbesartan 75 mg twice
daily, irbesartan 150 mg o.d., placebo) [37].
160
150
140
130
Hourly ABP
(mm Hg)
120
100
90
80
70
1 3
comparison), with greater reductions observed with
the 150/300 mg regimen (reduction in SeDBP, 10.5
mm Hg). Fifty-three percent of patients achieved
normalised blood pressure with this higher dose
regimen.
To further assess the relationship between irbesartan
dose and antihypertensive effectiveness, results of
eight double-blind, randomised, placebo-controlled
trials were pooled [36]. In these studies, patients (n =
2955) with mild-to-moderate hypertension were
treated with irbesartan daily doses of 1 mg to 900 mg
or placebo for 6 - 8 weeks. There was a clear relation-
ship between irbesartan (log) dose and blood
pressure lowering at the assessment (Figure 6). At
dosages of 150 mg o.d. and greater, irbesartan
provided consistent statistically and clinically signifi-
cant decreases in blood pressure. Irbesartan 150 mg
provided placebo-subtracted reductions in trough
seated systolic blood pressure (SeSBP) and SeDBP of
approximately 8 mm Hg and 5 mm Hg, respectively.
Antihypertensive effects plateaued at doses above 300
mg daily. Therapeutic response was also assessed in
this pooled analysis, and showed a similar relation-
ship between irbesartan dose and proportion of
patients responding (defined as SeDBP < 90 mm Hg or
reduction from baseline ≥ 10 mm Hg). Fifty-six
percent of patients responded to an irbesartan dose of
150 mg daily.
Blood pressure lowering with irbesartan over the full
24 h interval was assessed using ambulatory blood
pressure (ABP) monitoring [37]. In a double-blind,
placebo-controlled trial, the effects of irbesartan at
dosages of 75 mg twice daily and 150 mg o.d. were
© Ashley Publications Ltd. All rights reserved.
Johnston 661
Placebo 150 mg q.d. 75 mg b.i.d.
ASBP
ADBP
5 7 9 11 13 15 17 19 21 23
Hour post-dose
compared with placebo (n ≅ 55 patients/group). After
eight weeks, each of the irbesartan 150 mg daily
regimens maintained significantly decreased ABP
over the full 24 h compared with placebo (Figure 7).
The effects of irbesartan 150 mg daily on ambulatory
systolic blood pressure, daytime ABP, and trough
blood pressure measurements obtained at office
visits, were also significant. The 75 mg twice daily and
150-mg o.d. dosing regimens produced equivalent
reductions in blood pressure. Thus, these data
demonstrated 24 h blood pressure control with
irbesartan and the appropriateness of o.d. dosing.
Irbesartan/hydrochlorothiazide
6.3.2
combination studies
Additional reductions in blood pressure have been
observed with the combination of irbesartan and
HCTZ in patients with hypertension. HCTZ added to
irbesartan resulted in further reductions in blood
pressure in patients whose blood pressure did not
normalise (SeDBP ≥ 90 mm Hg) after eight weeks of
therapy with double-blind treatment with placebo or
irbesartan (n = 126) [38]. The addition of open-label
HCTZ 12.5 mg daily to irbesartan therapy produced
further reductions in blood pressure within a two
week period, which increased with increasing
irbesartan doses (incremental reductions in SeDBP of
1.6, 2.9, 4.2, and 7.7 mm Hg with placebo, irbesartan
100 mg, irbesartan 200 mg, and irbesartan 300 mg o.d.,
respectively).
Similarly, the addition of irbesartan to HCTZ resulted
in further blood pressure reductions in patients
unresponsive to HCTZ alone. Patients who were
Exp. Opin. Invest. Drugs (1999) 8(5)
662 Irbesartan: a pharmacologic and clinical review
Figure 8: Additive antihypertensive effects of irbesartan com-
bined with hydrochlorothiazide (HCTZ) [41].
0
-2
-4
-6
-8
-10
Change in BP -12
(mm Hg) -14
-16
-18
-20
-22
-24
-26
0 10
100
200
25
Dose of irbesartan (mg)
300
unresponsive to HCTZ 25 mg o.d. for four weeks (n =
238) were randomised to receive double-blind
placebo or irbesartan (75 mg o.d. titrated to 150 mg
o.d. after six weeks as needed) in combination with
HCTZ for an additional 12 weeks [39]. At week 12, the
mean reductions in trough SeSBP/SeDBP were 11.1
and 7.2 mm Hg greater with irbesartan/HCTZ
compared with placebo/HCTZ. The percentage of
patients whose blood pressure was normalised
(SeDBP < 90 mm Hg) was significantly greater for the
irbesartan/HCTZ combination (67% vs. 29% for
placebo/HCTZ), as was the percentage of responders
(SeDBP < 90 mm Hg or ≥ 10 mm Hg reduction from
baseline) (77% vs. 32%, respectively). In both of these
studies, the combination of irbesartan/HCTZ was
well-tolerated and there was no increased discon-
tinuation from therapy with the combination
compared with each single-agent therapy [38,39].
In a parallel-group, placebo-controlled trial, 815
patients were randomised to o.d. placebo, HCTZ 12.5
mg, or irbesartan 75 mg or 150 mg alone or combined
with HCTZ 12.5 mg [40]. The combination of
irbesartan and HCTZ produced reductions in blood
pressure superior to the individual components.
Reductions from baseline in SeSBP/SeDBP were
9.1/8.2 mmHg with HCTZ and 11.9/9.7 mmHg with
irbesartan 150 mg, while the combination resulted in a
reduction of 16.1/12.0 mmHg.
© Ashley Publications Ltd. All rights reserved.
The additive effects of irbesartan and HCTZ were also
demonstrated in a double-blind, placebo-controlled
matrix study [41]. Patients (n ≅ 40 patients/treatment
group) were randomised to receive placebo, or one of
three irbesartan doses (37.5 mg, 100 mg, 300 mg)
0 combined with placebo or one of three HCTZ doses
-5 (6.25 mg, 12.5 mg, 25 mg) for eight weeks. The results
0 of this study further documented the relationship
-2 -10
-4 between irbesartan dose and reduction in blood
-6
-8
-15
pressure, as well as demonstrating that the combina-
-10
-12
-20 tion of irbesartan and HCTZ resulted in greater blood
-14
-25
pressure reductions than with either irbesartan or
-16
-18 HCTZ alone (Figure 8).
-20
-22
-24
The combination of irbesartan and HCTZ was
-26
effective over the full 24-hour interval, as
0
5
demonstrated by ABP monitoring [42].
15 Dose of HCTZ (mg)
20
6.3.3 Long-term effectiveness of irbesartan
No diminution of long-term effectiveness of irbesartan
was seen in an open-label extension trial in patients
with mild-to-moderate hypertension (n = 171) [43].
Continued reduction in blood pressure was seen with
irbesartan for up to 12 months, and a total of 91% of
patients achieved normalised blood pressure (SeDBP
< 90 mm Hg) at this timepoint. Sixty-nine percent of
patients achieved normalisation with irbesartan
monotherapy, and 22% with irbesartan-based
combination therapy. The excellent long-term
response of irbesartan was also documented in
pooled data from five randomised trials in patients
with mild-to-moderate hypertension (n = 1006) [44].
At month 12, mean reduction in SeSBP/SeDBP was
-21/-16 mm Hg, with a response rate (SeDBP < 90 mm
Hg or ≥ 10 mm Hg reduction from baseline) of 90%
and a normalisation rate (SeDBP < 90 mm Hg) of 83%.
Sixty-two percent of patients were receiving only
irbesartan monotherapy, and an additional 22% were
receiving irbesartan/HCTZ only. In a long-term
extension of two double-blind, placebo-controlled
studies (n = 1098), the combination of irbesartan and
HCTZ maintained its effectiveness throughout the
course of the 12-month trial [45]. Therapeutic
response (SeDBP < 90 mm Hg or ≥ 10 mm Hg
reduction) was achieved in 90% of patients at month
12, with a normalisation rate (SeDBP < 90 mm Hg) of
83%. Adjunctive therapy was used in < 12% of
irbesartan/HCTZ-treated patients.
6.3.4 Controlled comparative studies
Randomised, controlled trials have compared the
antihypertensive effects of irbesartan with drugs from
Exp. Opin. Invest. Drugs (1999) 8(5)
 Johnston 663
Figure 9: Effects of irbesartan and enalapril on reduction in Figure 10: Effects of irbesartan 75 - 150 mg (± other antihy-
seated diastolic blood pressure (SeDBP): (a) irbesartan 75 mg pertensive agents) vs. atenolol 50 - 100 mg (± other antihyper-
to 300 mg vs. enalapril 10 - 40 mg in mild-to-moderate hyper- tensive agents) on reduction in seated diastolic blood pressure
tension [46] ; (b) irbesartan 150 - 300 mg (± other antihyper- (SeDBP) in mild-to-moderate hypertension [48].
tensive agents) vs. enalapril 20 - 40 mg (± other
antihypertensive agents) in severe hypertension [47].
a.
0 Irbesartan regimen

Enalapril regimen
SeDBP (mm Hg)

-5
Change from
baseline in

0
-10

-3 Irbesartan regimen

-15 Atenolol regimen

SeDBP (mm Hg)

-6

Change from
baseline in
-20
-9
0 2 4 6 8 10 12

Week
-12

b.
-15
0
Irbesartan regimen

Enalapril regimen
-18
-10
0 2 4 6 8 10 12 14 16 18 20 22 24
SeDBP (mm Hg)
Change from
baseline in

Week

-20

-30

-40
0 1 2 4 6 8 10 12

Week

other antihypertensive classes, including the ACE o.d. [47]. Treatment was initiated at 150 mg and 20 mg,
inhibitor enalapril, the β-blocker atenolol, the calcium respectively, and the doses were doubled to 300 mg
antagonist amlodipine, the diuretic HCTZ, and the and 40 mg if needed, to achieve blood pressure
AIIRA losartan. The results of these comparative trials normalisation (SeDBP < 90 mm Hg). Additional
follow. open-label medications were added after titration, if
necessary. As in the study above [46], the irbesartan-
Irbesartan was compared with enalapril in patients
and enalapril-based regimens produced similar
with mild-to-moderate hypertension [46] and in
reductions in trough SeDBP throughout the 12-week
patients with severe hypertension [47]. In the former
study (Figure 9b). At the end of the study, the mean
study, patients with SeDBP 95 - 110 mm Hg were
reductions in systolic and diastolic blood pressures
randomised to receive double-blind irbesartan (n =
with both regimens were 40 mm Hg and 30 mm Hg,
98) or enalapril (n = 102) o.d.. Doses were initiated at
respectively. The proportions of patients who were
75 mg and 10 mg, respectively, which were sequen-
normalised were also similar (59% and 57% for
tially doubled (final doses of 300 mg and 40 mg,
irbesartan- and enalapril-treated patients, respec-
respectively) in order to achieve normalised blood
tively); however, the irbesartan-treated patients
pressure (SeDBP < 90 mm Hg). Throughout the study
tended to achieve normalisation sooner than the
and at the 12-week end-point, irbesartan and enalapril
enalapril-treated patients (22% and 14%, respectively,
produced similar reductions in blood pressure
at week 4). Thus, the irbesartan regimens used in
(Figure 9a). Mean reductions in systolic and diastolic
these studies provided at least equivalent effective-
blood pressure were approximately 19 mm Hg and 13
ness as full-dose enalapril in those with
mm Hg, respectively, for both regimens at week 12.
mild-to-moderate hypertension and severe hyperten-
The proportions of patients normalised (SeDBP < 90
sion, with superior tolerability (see Section 7).
mm Hg) were also similar (66% with irbesartan, 63%
with enalapril).
Irbesartan was also compared with atenolol in
In the latter study, patients with severe hypertension patients with mild-to-moderate hypertension [48].
(SeDBP 115 - 130 mm Hg; mean blood pressure, Patients were randomised to receive double-blind
176/119 mm Hg) were randomised to receive irbesartan (n = 110) or atenolol (n = 121) at initial o.d.
double-blind irbesartan (n = 121) or enalapril (n = 61) dosages of 75 mg and 50 mg, respectively, for 12
© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs (1999) 8(5)
664 Irbesartan: a pharmacologic and clinical review
Figure 11: Effects of irbesartan 150 mg vs. amlodipine 5 mg
and placebo on reduction in seated diastolic blood pressure
(SeDBP) in elderly patients with mild-to-moderate hyperten-
sion.
0 Two randomised, double-blind studies compared the
Placebo (n = 68)
Irbesartan 150 mg (n = 70)
-2
Amlodipine 5 mg (n = 71)
-4
SeDBP (mm Hg)
Change from
baseline in
-6
-8
-10
-12
-14
2 4 8
Weeks
weeks. At week 6, doses could be doubled if blood
pressure was not normalised (SeDBP < 90 mm Hg),
and at week 12 or thereafter until week 24, additional
open-label antihypertensive therapies could be added
to achieve normalisation. At week 12 (monotherapy
only) and throughout the study, the irbesartan- and
atenolol-based regimens produced similar reductions
in blood pressure (Figure 10). normalisation rates
were 61% and 55% for irbesartan and atenolol, respec-
tively at week 12, which increased to 73% and 75%,
respectively at week 24. Thus, irbesartan provides
comparable efficacy to full doses of atenolol, with
superior tolerability (see Section 7).
Irbesartan was compared with amlodipine in elderly
patients with mild-to-moderate hypertension [data on
file, Bristol-Myers Squibb/Sanofi] and in hypertensive
patients with Type 2 diabetes and proteinuria [49]. In
the elderly, reductions in SeDBP at week 8 (the
primary end-point) were similar with irbesartan 150
mg (-12.1 mm Hg) and amlodipine 5 mg (-11.9 mm
Hg) (Figure 11). In patients with diabetes and
proteinuria, results of a double-blind, randomised
pilot study showed that an irbesartan regimen (75 -
300 mg o.d., n = 24) and an amlodipine regimen (2.5 -
10 mg o.d., n = 23) produced comparable reductions
in SeDBP throughout the 12-week study [49]. Only
irbesartan, however, provided beneficial renal effects
(see Section 6.4.1).
In addition to examining the effects of irbesartan
when combined with HCTZ, two double-blind,
placebo-controlled studies compared the antihyper-
tensive effects of irbesartan to HCTZ [43]. Mean
reductions in SeDBP were 9.7 mm Hg for irbesartan
150 mg and 8.2 mm Hg for HCTZ 12.5 mg. Reductions
© Ashley Publications Ltd. All rights reserved.
in SeSBP were 11.9 mm Hg and 9.1 mm Hg,
respectively.
antihypertensive effectiveness of the AIIRA agents,
irbesartan and losartan, in patients with mild-to-
moderate hypertension. In a parallel-group, placebo-
controlled trial (n = 567), the effects of irbesartan on
blood pressure were compared with those of the
maximum recommended dosage of losartan (100 mg
o.d.) [50]. At the end of the eight week study,
reduction in trough SeDBP was 3.0 mm Hg greater
with irbesartan 300 mg than with losartan 100 mg
(Figure 12a) and reduction in trough SeSBP was 5.1
mm Hg greater with irbesartan 300 mg than with
losartan 100 mg (p each < 0.01). The effects of
irbesartan 150 mg o.d. were similar to those of
losartan throughout the study. All therapies were
well-tolerated.
Irbesartan and losartan were also compared in an
elective titration study, in which patients (n = 432)
were randomised to initial dosages of 150 mg or 50 mg
o.d., respectively [51]. Doses were doubled at week 4
if blood pressure was not normalised (SeDBP ≥ 90
mm Hg), and HCTZ 12.5 mg was added at Week 8 if
normalisation was still not achieved (upon the
addition of HCTZ, the dose of losartan was decreased
from 100 mg to 50 mg to match the marketed
losartan/HCTZ combination product). At week 8, the
reduction in SeDBP with irbesartan monotherapy
(10.2 mm Hg) was significantly greater than with
losartan monotherapy (7.9 mm Hg) (p < 0.02) (Figure
12b). At week 12, with the addition of HCTZ,
reductions in trough SeSBP/SeDBP remained greater
with the irbesartan regimen (18.0/13.8 mm Hg) than
with the losartan regimen (13.9/10.8 mm Hg) (p < 0.02
for SeSBP, p < 0.002 for SeDBP). The percentage of
patients whose blood pressure responded (trough
SeDBP < 90 mm Hg or reduction ≥ 10 mm Hg) was
greater with irbesartan (78%) than with losartan (64%)
(p < 0.01). A weakness of this study is that the losartan
dose was decreased with the addition of diuretic;
whether the same results would have been obtained
by maintaining losartan at 100mg is unknown.
In summary, comparative trials demonstrate that
irbesartan produces blood pressure lowering effects
comparable to or exceeding full doses of leading
antihypertensive agents among several pharma-
cologic classes.
Exp. Opin. Invest. Drugs (1999) 8(5)
 Johnston 665
Figure 12: Effects of irbesartan vs. losartan on reduction in seated diastolic blood pressure (SeDBP) in mild-to-moderate hyperten-
sion: (a) fixed-dose study of irbesartan 150 mg and 300 mg vs. losartan 100 mg [50] ; (b) elective titration study of irbesartan 150 - 300
mg (± HCTZ) vs. losartan 50 - 100 mg (± HCTZ) [51].
a. 0
Placebo

Losartan 100 mg

Irbesartan 150 mg
-3
Irbesartan 300 mg

-6
Change from
baseline in

(mm Hg)
SeDBP

-9

*
†
-12
* p < 0.01 vs. losartan
†

p = 0.017 vs. losartan

*

-15
0 1 2 4 8

Week
b. 0 Irbesartan

Losartan
-2

-4
Change from
baseline in

-6
(mm Hg)
SeDBP

-8

-10

-12 *
* p < 0.02
†

p < 0.002
-14
†

-16
0 4 8 12
Week

6.4 Preservation of organ function effects, as evidenced by increased creatinine

clearance and decreased urine protein excretion,
Hypertension is a major risk factor for the develop-
whereas amlodipine decreased creatinine clearance
ment of secondary end-organ damage, including
(p < 0.01 vs. irbesartan) and slightly increased urine
cardiac and renal disease. In animal models of
protein excretion. Adverse events and serious adverse
hypertension and renal damage, irbesartan improved
events also occurred more frequently with
glomerular sclerosis and renal injury [52,53] in
amlodipine treatment than with irbesartan treatment.
addition to lowering blood pressure. Preclinical
A large multicentre, placebo-controlled study is
studies also demonstrated the effectiveness of
currently underway (the Irbesartan Diabetic Nephro-
irbesartan in retarding the development of ventricular
pathy Trial, or IDNT) to further assess the effects of
and vascular hypertrophy [52] and heart failure [54].
irbesartan on morbidity, mortality and renal function
The clinical effects of irbesartan on renal and cardio-
in patients with hypertension and Type 2 diabetes
vascular protection were therefore evaluated in
with nephropathy [55].
double-blind studies in patients with hypertension.

6.4.1 Renal protection 6.4.2 Cardiac protection

Irbesartan was compared with amlodipine in Left ventricular hypertrophy (LVH) is a major
hypertensive patients with Type 2 diabetes and independent risk factor for cardiovascular disease and
proteinuria [49]. Results from a double-blind, random- a significant predictor of mortality. Irbesartan therapy
ised, pilot study showed that although irbesartan (75 - resulted in regression of LVH which occurred sooner
300 mg o.d., n = 24) and amlodipine (2.5 - 10 mg o.d., and to a greater extent than atenolol, despite similar
n = 23) produced comparable reductions in SeDBP, reductions in blood pressure, when compared in a
there were differences in the effects of these agents on randomised, comparative study in hypertensive
renal function. Irbesartan provided beneficial renal patients with LVH (n = 115) [56].
© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs (1999) 8(5)
666 Irbesartan: a pharmacologic and clinical review
Table 2: Lack of relationship between irbesartan dose and incidence of adverse events [60].
% of Patients
Irbesartan Daily Dose
< 75 mg 75 - 100 mg 150 - 200 mg
(n = 452) (n = 539) (n = 595)
Adverse events 54.6 52.7 52.6
Adverse drug 19.9 18.2 20.3
experiences
Discontinuations 4.4 2.0 3.0
due to adverse
events
Serious adverse 1.3 1.1 1.2
events
§ Includes irbesartan < 75 - 900 mg.
Irbesartan induced acute and long-term improve-
ments in haemodynamic parameters in patients with
heart failure when evaluated in a double-blind
dose-ranging study (n = 218) [57]. Decreases in
pulmonary capillary wedge pressure and mean
arterial pressure, and increases in left ventricular
ejection fraction (LVEF) occurred with irbesartan after
12 weeks treatment, with no change in heart rate.
Irbesartan also prevented further worsening of
disease as evidenced by fewer discontinuations from
the study due to worsening heart failure. Irbesartan
improved exercise tolerance test (ETT) parameters
and LVEF in a comparative (vs. lisinopril) pilot study in
patients with mild-to-moderate heart failure (n = 134)
[58]. In another placebo-controlled pilot study in
patients with mild-to-moderate heart failure (n = 109),
irbesartan combined with conventional therapy
(including ACE inhibitors) produced favourable
trends in ETT parameters and LVEF [59].
7. Safety and tolerability
Adverse event data were pooled from nine placebo-
controlled irbesartan monotherapy studies to
examine the relationship between irbesartan dose
and tolerability [60]. There was no association
between irbesartan dose and the incidence of adverse
events or the rate of discontinuation from therapy as a
result of adverse events (Table 2). The adverse events
profile with irbesartan (n = 1965) at doses up to 900
mg daily, which is three times the maximum
recommended daily dose, was similar to that with
placebo (n = 641). Importantly, there was no differ-
ence in the incidence of any adverse event between
© Ashley Publications Ltd. All rights reserved.
Any Irbesartan§ Placebo
300 mg
(n = 288) (n = 1,965) (n = 641)
50.0 56.2 56.5
18.8 21.3 20.0
1.7 3.3 4.5
1.0 1.0 1.9
irbesartan and placebo, including cough (placebo,
2.7%; irbesartan, 2.8%). Also, there was no evidence
of hypotension or its symptomatic equivalent, no
evidence of first-dose effects with irbesartan, and no
rebound hypertension upon withdrawal of irbesartan
therapy.
Examination of laboratory data showed no reports of
neutropenia with irbesartan. There was also no differ-
ence in the incidence of elevated liver function test
values between irbesartan and placebo when data
from all patients treated in double-blind, placebo-
controlled trials were analysed (n = 2544).
In comparative trials, irbesartan had a tolerability
profile superior to that of other antihypertensive
classes. Irbesartan therapy was associated with signifi-
cantly less cough than enalapril (2.5% vs. 13.1%,
respectively; p = 0.007) [47], and with less bradycardia
and fatigue, and fewer discontinuations due to
adverse events compared with atenolol [48]. With the
combination of irbesartan and HCTZ, there were no
significant first-dose or hypotension-related adverse
events and no added tolerability concerns in short-
term [41,42] or long-term [45] trials.
8. Regulatory affairs
Irbesartan is marketed for clinical use in the United
States and in more than 20 other countries worldwide.
It is indicated as monotherapy and in combination
with HCTZ for the treatment of adult patients with
hypertension. It has not been withdrawn from
marketing in any country.
Exp. Opin. Invest. Drugs (1999) 8(5)

9. Clinical role and future studies
The choice of initial antihypertensive therapy should
be individualised, based on the patients’ needs, their
comorbid medical conditions, and the goal of
improving their adherence to therapy [5]. With the
side-effects commonly seen with the diuretic and
β-blocker classes of agents, it is appropriate to select
an agent with a favourable tolerability profile [61].
The efficacy of irbesartan in reducing blood pressure
has been clearly established. Irbesartan demonstrates
a clear relationship between dose and antihyperten-
sive response, and provides consistent blood pressure
lowering over the full 24-hour period. Its effectiveness
in reducing blood pressure is comparable to, or
exceeds that of, other leading antihypertensive
agents, as demonstrated in randomised, controlled
clinical trials. Irbesartan also has shown renoprotec-
tive and cardiovascular protective effects in
preliminary clinical trials.
AIIRAs appear to offer clinical benefit over ACE
inhibitors, particularly with regard to safety and
tolerability. They do not induce cough, a characteristic
side-effect of ACE inhibitors. There are also no signifi-
cant safety concerns with irbesartan, and the AIIRAs
as a class, as there are with other drug classes, such as
oedema and headache with calcium antagonists,
bradycardia and fatigue with β-blockers, and
metabolic abnormalities with diuretics. These benefits
may translate into better patient compliance with their
antihypertensive medication regimen, longer
continuation with therapy, and hence, improved
overall effectiveness in controlling blood pressure
and its related morbidity and mortality.
Irbesartan possesses pharmacokinetic and pharmaco-
dynamic features that may translate into clinical
benefits in comparison with other AIIRAs. These
include:
• consistent and extensive oral bioavailability
• no necessary biotransformation to an active
metabolite
• prolonged half-life
• high volume of distribution
• no effects of renal or hepatic impairment, of gender
or age on pharmacokinetics
• low potential for clinically significant drug
interactions
© Ashley Publications Ltd. All rights reserved.
Johnston 667
• dose-related pharmacodynamic effects.
Ongoing trials are currently being conducted to
evaluate further the long-term effectiveness and safety
of irbesartan in managing blood pressure, as well as
the effects of irbesartan on morbidity and mortality in
high-risk hypertensive patients with diabetic
nephropathy.
10. Conclusions
Irbesartan is an AIIRA that provides insurmountable,
dose-related blockade of AT1 receptors for effective,
reliable 24 h blood pressure control with o.d. dosing.
Irbesartan has been shown to be as effective as, and
better tolerated than, other leading antihypertensive
classes of agents. Given its excellent dose response in
antihypertensive effectiveness, while maintaining a
tolerability profile similar to placebo at all doses,
irbesartan offers a good, alternative choice for the
long-term management of hypertension.
Acknowlegements
The author would like to thank Linda Mattucci
Schiavone for her editorial contributions to this
manuscript.
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•• This analysis of data from nine randomised, placebo-
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Colin I Johnston
University of Melbourne, Department of Medicine, Austin Campus,
Heidelberg 3084, Victoria, Australia
Tel.: +61 3 9496 5198; Fax: +61 3 9457 5485;
Exp. Opin. Invest. Drugs (1999) 8(5)