Cardiovascular Drug Reviews

Vol. 18, No. 2, pp. 127–154

© 2000 Neva Press, Branford, Connecticut

A Review on Telmisartan:
A Novel, Long-Acting
Angiotensin II-Receptor Antagonist

Wolfgang Wienen, 1Michael Entzeroth, 2Jacobus C. A. van Meel,

Joachim Stangier, Ulrich Busch, Thomas Ebner, Jochen Schmid,
Horst Lehmann, 3Kandace Matzek, 4Joan Kempthorne-Rawson,
3Volker Gladigau, and Norbert H. Hauel

Departments of Chemical and Pharma Research,

Boehringer Ingelheim, Biberach, Germany;
3
Boehringer Ingelheim GmbH, Ingelheim, Germany;
4
Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA;
Present address:
1
CEREP, Celle l’Evescault, France;
2
Boehringer Ingelheim Austria GmbH, Vienna, Austria

Key Words: ABPM—Angiotensin II (AT1) receptor antagonist—Hyperten-

sion—Telmisartan.

ABSTRACT
Telmisartan is a potent, long-lasting, nonpeptide antagonist of the angiotensin II type-1
(AT1 ) receptor that is indicated for the treatment of essential hypertension. It selectively
and insurmountably inhibits stimulation of the AT1 receptor by angiotensin II without af-
fecting other receptor systems involved in cardiovascular regulation. Very high lipophilic-
ity, a unique feature of telmisartan, coupled with a high volume of distribution, indicate
that the compound offers the clinically important advantage of good tissue penetration.
Telmisartan is not a prodrug and has a longer terminal elimination half-life than other
commercially available sartans (~24 h), making it suitable for once-daily dosing. The
compound is not metabolized by cytochrome P450 isoenzymes and has a low risk for
P450-based drug interactions. In animal models, telmisartan exhibits pronounced cardio-
and reno-protective effects in animals with severe, essential hypertension. In clinical
studies, telmisartan shows comparable antihypertensive activity to members of other
major antihypertensive classes, such as ACE inhibitors, beta blockers and calcium antago-
nists. These trials have confirmed the placebo-like safety and tolerability of telmisartan in
hypertensive patients. Based on these data, telmisartan offers advantages over other sar-
tans and represents an important new treatment option for hypertension.

Address correspondence and reprint requests to: Dr. Wolfgang Wienen, Department of Pharma Research,
Boehringer Ingelheim Pharma KG, D-88397 Biberach an der Riss, Germany.
E-mail: wolfgang.wienen@bc.boehringer-ingelheim.com.

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128 W. WIENEN ET AL.

INTRODUCTION

The renin-angiotensin system plays an important role in the development and mainte-
nance of hypertension and hypertensive heart disease. Blockade of angiotensin II (AII) re-
ceptors represents a logical approach to the selective inhibition of the pressor response of
the renin-angiotensin system and, therefore, to the reduction of blood pressure (35). The
AT1 -receptor subtype accounts for virtually all known cardiovascular effects of AII (47),
whereas the function of the AT 2 receptor is less clear at present (36).
Angiotensin converting enzyme (ACE) inhibitors, widely used to treat hypertension
and concomitant renal diseases, and congestive heart failure, block the enzymatic con-
version of angiotensin I to AII, the final effector of the renin-angiotensin system.
However, in addition to preventing the formation of AII, ACE inhibitors also reduce the
degradation of bradykinin and substance P. It has been hypothesized that the class-specific
side effect of ACE inhibitors (cough) may be related to this lack of specificity (42).
Moreover, alternative pathways exist for the generation of AII, which may be active even
when ACE is inhibited (46,56). Therefore, research efforts have been directed towards the
development of nonpeptide AII receptor antagonists, which in turn might be devoid of
ACE-inhibitor cough and could result in a more complete blockade of the entire renin-an-
giotensin system. Losartan, as the protagonist of selective and orally active, nonpeptide
angiotensin receptor antagonists, has demonstrated efficacy in the preclinical (50) and
clinical setting (22). However, this compound has to undergo biotransformation to the
more active metabolite EXP 3174, which is mainly responsible for the pharmacodynamic
effects.
Telmisartan (BIBR 277 SE, Micardis ®) was identified as a direct-acting AII receptor
antagonist. On this basis, telmisartan was expected to possess therapeutic potential in the
pharmacotherapy of hypertension. The results presented here established that telmisartan
is a potent and selective antagonist for the AT1 receptor subtype. Telmisartan exerts potent
and sustained antagonism of AII-mediated pressor responses in vivo, and effectively
lowers blood pressure in animal models of hypertension as well as in humans. The hypo-
tensive effects are of long duration. The compound exhibits favorable effects on renal
function in laboratory animals and is not associated with significant ancillary pharmaco-
logical effects, and limited clinical data suggest potential superiority of telmisartan over
losartan 50 mg once daily (34).

CHEMISTRY

Telmisartan (BIBR 277) is chemically described as [1,1¢-biphenyl]-2-carboxylic acid,

4¢-[(1,4¢-dimethyl-2¢-propyl[2,6¢-bi-1H-benzimidazol]-1¢-yl)methyl]-(CAS) (Fig. 1). It is
a white crystalline powder with a molecular weight of 514.6 and a melting point of 261 to
263°C (47). The solubility of telmisartan in aqueous solutions is strongly pH-dependent,
with maximum solubility observed at high and low pH. In the range of pH 3–9 it is only
poorly soluble. Telmisartan is active as such: it is not a prodrug. The telmisartan molecule
is unusually stable. No Phase I-type metabolism has been observed.
Among the AII antagonists, telmisartan is the most lipophilic compound with a par-
tition coefficient log P = 3.2 (n-octanol/buffer at pH 7.4) (Table 1). Due to its physico-
chemical properties, telmisartan shows excellent oral absorption and tissue penetration.

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TABLE 1. Lipophilicity
of Various AII Antagonists
Compound log P*
EXP 3174** –2.45
Valsartan –0.95
Candesartan –0.96
Irbesartan +1.48
Telmisartan +3.20
* log P describes the partition coeffi -
cient (n-octanol/buffer at pH 7.4).
FIG. 1. Chemical structure of telmisartan. ** EXP 3174 is the active metabolite
of losartan.

RECEPTOR BINDING STUDIES

The interaction of telmisartan with AII type-1 (AT1) and type-2 (AT2 ) receptors was de-
termined in radioligand binding experiments (61). Inhibition of 125I-labeled AII binding
by telmisartan revealed a high affinity of this compound for AT1 receptors in rat lung
tissue preparations (13), with a K i value of 3.7 nM. In contrast, the AT1-selective antag-
onist losartan and its active metabolite EXP 3174 are less potent, with K i values of
23.7 nM and 10.4 nM, respectively (13). Beneficial effects on renal function may be pre-
dicted from the observation that telmisartan potently interacts with rat renal AT1 receptors
with a Ki value of 14.4 nM. By comparison, losartan shows 5-fold lower affinity in this
tissue (62).
The binding of telmisartan to AT1 receptors is competitive, as demonstrated in ligand
saturation experiments (62), and reversible, as shown in radioligand binding studies with
3H-labeled telmisartan (Fig. 2). In these experiments, telmisartan dissociates slowly from

AT1 receptors, with a half-life (t1/ 2) of 5.9 h.

Telmisartan does not bind to AT2 receptors. Thus, telmisartan is a potent and selective
antagonist of AII type-1 (AT1) receptors. Studies in rat adrenal medulla tissue preparations
revealed that PD 123.177, a selective AT2 receptor antagonist, completely inhibited
125I-AII binding with a K value of 76.0 nM. However, telmisartan, as well as losartan,
i
were ineffective in high concentrations and had K i values of > 10,000 nM (Table 2).
The specificity of telmisartan was confirmed by the lack of interaction with a variety of
other receptors or enzymes relevant for cardiovascular regulation (61).

PHARMACOLOGY

Functional Antagonism of AII

In vitro studies
In vascular rings of the rabbit aorta, telmisartan effectively antagonized the effect of
AII, producing a rightward shift in the concentration-contractile response curve for AII
(Fig. 3) (61). Both the maximal contractile response and the slope of the response curve
were decreased in the presence of 10, 100 or 1000 nM telmisartan; the K B for telmisartan,

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130 W. WIENEN ET AL.

FIG. 2. Specific binding of [3 H]telmisartan to rat lung AT1 receptors (closed circle). In a parallel experiment,
1 mM unlabeled antagonist was added after equilibrium was achieved (arrow) and the dissociation of
[ 3H]telmisartan was followed (open circle).

TABLE 2. Inhibition of [125I]-Angiotensin II Binding to Rat Lung (AT 1)

and Adrenal Medulla Membrane (AT2) Preparations
Ki (nM) ± S.E.M. Hill coefficient
AT1 receptor
AII 1.2 ± 0.4 1.09 ± 0.04
Telmisartan 3.7 ± 0.7 0.87 ± 0.07
Losartan 23.7 ± 2.5 0.99 ± 0.01
EXP 3174 10.4 ± 0.9 0.88 ± 0.06
PD 123.177 > 10,000 —
AT2 receptor
AII 0.31 ± 0.01 1.01 ± 0.02
Telmisartan > 10,000 —
Losartan > 10,000 —
PD 123.177 76.0 ± 16.6 0.86 ± 0.06

calculated by modified Schild analysis, was 0.33 nM. No agonistic activity was observed
for any of the concentrations of telmisartan studied.
The inhibitory effects of telmisartan on the AII-induced contraction appeared to be spe-
cific, since telmisartan concentrations up to 10,000 nM did not inhibit contractions in-
duced by norepinephrine or K + gradient depolarization. The inhibitory effect of telmisar-
tan on AII-mediated contraction persisted even after several wash-out procedures.
To demonstrate that the antagonism of telmisartan is of a reversible nature, receptor
protection studies were performed in the presence of both telmisartan and the surmount-
able antagonist losartan according to previously published results (60). In tissues incu-

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 TELMISARTAN 131

FIG. 3. Effect of telmisartan on AII-induced contractile response in isolated rabbit aortic rings. Values are given
as percentage of the control maximum contractile force: numbers of experiments performed are given in paren-
theses. From ref. 61.

bated with telmisartan, the AII concentration-response curve was markedly suppressed
and displaced to the right. In preparations that were co-incubated with losartan (Fig. 4),
the AII concentration-response curves were displaced upward, in proportion to the con-
centration of losartan. Similar results have been described previously, in studies that used
different peptide and nonpeptide AII antagonists (60,67). If telmisartan had bound cova-
lently (irreversibly) to the angiotensin receptor, then co-incubation with the competitive
antagonist would not have been expected to exert any effect on the maximum response to
AII. Therefore, these functional data are in accordance with results from the receptor
binding studies, providing further evidence that telmisartan is a potent and long-lasting,
insurmountable, but reversible, antagonist at angiotensin AT1 receptors.

In vivo studies
In pithed rats, telmisartan doses of 0.1, 0.3, and 1.0 mg/kg i.v. shifted the AII dose-
pressor response curve downward and to the right with an ED50 of 0.23 mg/kg (61). Addi -
tional experiments showed that the pressor response to AII was inhibited for more than
24 h after a single dose of 1 mg/kg (Fig. 5). However, recovery of the pressor response
was complete within 48 h after administration of telmisartan. Similar results were ob-
tained with EXP 3174, the active metabolite of losartan (not shown). Our results show that
receptor function in vivo recovers completely, albeit slowly, after administration of
telmisartan.
The AII pressor response was also consistently inhibited in anesthetized rats (61) and
conscious dogs (63) after either intravenous or oral administration of telmisartan.

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132 W. WIENEN ET AL.

FIG. 4. Effect of solvent, telmisartan or co-incubation of telmisartan in the presence of losartan on the log con-
centration-contractile response curve for AII in rabbit aortic rings; numbers of experiments are given in paren-
theses. From ref. 61.

Blood Pressure Lowering Effects

Conscious monkeys
The hemodynamic effects of telmisartan were investigated in conscious, sodium-de-
pleted cynomolgus monkeys (66). These animals are normotensive, but as a consequence
of sodium depletion have increased plasma renin activity and elevated plasma levels of
AII. Telmisartan (0.3 to 10.0 mg/kg p.o.) caused prompt decreases in blood pressure in
this model (Fig. 6). The onset of the hypotensive effect was rapid and sustained for at least
3.5 h. There were no effects on heart rate. The hypotensive effect was similar to that ob-
tained with a maximally effective dose of the ACE inhibitor enalapril (0.3 mg/kg i.v.).
For comparison, losartan lowered blood pressure to a similar level after 30 mg/kg p.o.,
but not at 10 mg/kg p.o., in these animals.

Renovascular hypertensive rats

In renal hypertensive rats, repeated oral administration of 1 mg/kg/d telmisartan over a
period of 4 days resulted in significant and sustained reductions in mean arterial blood
pressure of 35 to 60 mm Hg (61).

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FIG. 5. Time-dependent effects of intravenous administration of telmisartan (1 mg/kg i.v.) on the log dose
pressor response curve of AII in pithed rats. Values are means ± S.E.M.

Another investigation utilizing these rats evaluated the hypotensive effects of telmisar-
tan when administered in the drinking water for 1 week at 1.0 mg/kg/d, followed by an
additional week after decreasing the dose to 0.3 mg/kg/d (Fig. 7). Telmisartan at
1.0 mg/kg/d lowered mean arterial blood pressure with a peak fall after 7 days of 38 ± 2
mm Hg. When the dosage of telmisartan was reduced to 0.3 mg/kg/d, mean arterial blood
pressure gradually increased. However, the maximum reduction with 0.3 mg/kg/d, after 7
days, was still 29 ± 5 mm Hg. Heart rate did not change with either treatment regimen.

Transgenic mREN2 hypertensive rats

Transgenic mREN2 rats are hypertensive but do not overexpress active renin in the
kidney, and have low levels of active renin in their plasma (43). These animals are highly
sensitive to pharmacologic manipulation of the renin-angiotensin system. Oral treatment
with telmisartan at a dose of 0.5 mg/kg/d for 1 week produced a significant reduction in

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134 W. WIENEN ET AL.

FIG. 6. The effect of telmisartan (0.1 to 10.0 mg/kg p.o.) on mean arterial blood pressure in conscious,
sodium-depleted cynomolgus monkeys. From ref. 66.

FIG. 7. Effect of oral administration, via the drinking water, of vehicle or telmisartan on mean arterial blood
pressure of renal hypertensive rats. Arrows indicate the start of the administration period for each dosage of
telmisartan.

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 TELMISARTAN 135

mean arterial pressure (MAP) (Fig. 8A). A stronger reduction in mean arterial blood
pressure was observed after 1 week of treatment with 1 mg/kg/d telmisartan, and in-
creasing the dose to 2 mg/kg/d for one week lowered MAP by a maximum of 72 mm Hg.
The effects of telmisartan were fully reversible and blood pressure was not significantly
different from pretreatment values nine days after withdrawal of telmisartan. Comparable,
albeit significantly smaller, hypotensive effects were observed for losartan in these trans-
genic animals. In addition, higher doses were needed to produce a relevant reduction in
blood pressure. After 1 week of treatment with the highest dose of losartan (4 mg/kg/d),
the maximum reduction in MAP was 33 mm Hg (Fig. 8B) (37).
The antihypertensive effect of telmisartan in mREN2 rats was also investigated in a
long-term study that employed three different doses of drug (Fig. 9) (4). No significant
change in blood pressure was observed in animals treated with the lowest dose
(0.1 mg/kg/d) at the end of the treatment period. However, in the presence of 1 mg/kg/d
and 3 mg/kg/d telmisartan, systolic blood pressure was lowered in a dose- and time-de-
pendent manner, reaching almost normotensive values with the highest dose after nine
weeks.
In addition, at the end of the study period, the heart weight:body weight ratio decreased
significantly from 4.3 in untreated animals to 3.5, 3.1, and 2.9 in the low-, medium-, and
high-dose telmisartan groups, respectively. AII telmisartan doses led to a decrease in the
diameter of cardiomyocyte muscle bundles. Moreover, the two higher doses decreased
muscle bundle diameter to normal size (5).
Aldosterone leads to sodium retention and volume overload and, in concert with AII,
has been demonstrated to induce or promote cardiac fibrosis (59). Interestingly, treatment
with all three doses of telmisartan reduced urinary aldosterone excretion significantly and
in a dose-dependent manner (Fig. 10), suggesting an additional beneficial effect of
telmisartan via suppression of the deleterious cardiac effects of aldosterone. Of note, even
the lowest dose of telmisartan, which did not significantly reduce blood pressure, substan-
tially decreased aldosterone levels.
The high glomerulosclerosis index and pronounced proteinuria observed in untreated
(mREN2)27 rats were markedly reduced by 9 weeks of treatment with telmisartan. The
glomerulosclerosis index decreased to normal levels even in the low-dose group, and
urinary albumin excretion fell in a dose-dependent fashion to levels of 4.6 ± 3.3 mg/24 h
with the high dose, which is within the normal range reported for Sprague–Dawley
rats (4).

Spontaneously hypertensive rats

Similar results were obtained in a 7-week study in spontaneously hypertensive rats of
the stroke-prone strain (SHPsp) (58). In this study, losartan and captopril were included as
comparator drugs at equieffective doses. Despite a similar reduction in blood pressure by
the comparator drugs, only telmisartan produced a significant reduction in left ventricular
mass compared with controls (Fig. 11).
Pronounced dose-dependent antihypertensive and renoprotective effects were also ob-
served after 8 months of treatment with 3 and 10 mg/kg telmisartan in hypertensive rats
with type 1 diabetes mellitus induced by streptozotocin (64).
These data demonstrate that telmisartan produces consistent and effective reduction in
blood pressure in animal models of renin-dependent and essential hypertension. In ad-

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136 W. WIENEN ET AL.

FIG. 8. Changes in mean arterial blood pressure of male (mREN) transgenic rats after administration of
telmisartan (A) or losartan (B) via drinking water. Arrows indicate start of applications for a 1-week period.
Adapted from ref. 37.

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 TELMISARTAN 137

FIG. 9. Effects of 9-week oral administration of telmisartan on systolic blood pressure in heterozygous male
TGR(mREN2)27 rats.

FIG. 10. Urinary aldosterone excretion of heterozygous male TGR (mREN2)27 rats at the end of an 8-week
treatment period with three doses of telmisartan (mean ± S.E.M.).

dition, the latter studies suggest that telmisartan has also pronounced cardio- and reno-
protective effects in animals with severe hypertension.

Renal Effects
Studies in the isolated perfused rat kidney have revealed that telmisartan increases
renal perfusate flow, urine flow and glomerular filtration rate in a concentration-dependent
manner (62). Further experiments in this model showed that telmisartan (0.1 and 1 mM)

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138 W. WIENEN ET AL.

50 mg 20 mg 10 mg
FIG. 11. Effects of 7-week oral treatment with telmisartan, losartan or captopril on blood pressure (A) and left
ventricular hypertrophy (B) in SHR-SP rats. *P < 0.05 vs. all treated groups in A and *P < 0.05 vs. controls in B.
Adapted from ref. 58.

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was also able to increase further the diuretic action of furosemide. Telmisartan (0.1 and
0.3 mg/kg i.v.) induced a dose-dependent increase in urine production and Na+ excretion
in anesthetized rats, while K + excretion was not affected (62).
In conscious dogs, single intravenous (0.03, 0.1, and 0.3 mg/kg i.v.) or oral (0.3, 1, and
3 mg/kg p.o.) administration of telmisartan significantly increased urine volume, and
sodium and chloride excretion. Potassium and creatinine excretion were not altered in
these experiments (49). These results suggest that telmisartan may exert favorable effects
on renal function.

Pharmacodynamics of the Metabolite

The pharmacodynamic effects of BIBR 277 SE 1-O-acylglucuronide, the metabolite of
telmisartan, were tested in a functional assay that employed the AII pressor response test
in anesthetized rats. BIBR 277 SE 1-O-acylglucuronide was found to have no significant
activity compared with that of the parent compound, telmisartan (65). Neither basal blood
pressure nor the increase in blood pressure induced by AII were affected by the presence
of the metabolite. It was concluded from this study that the metabolite of telmisartan is
devoid of any effect on the cardiovascular system and does not possess AII antagonistic
activity.

PHARMACOKINETICS
The pharmacokinetic profile of telmisartan has been studied in human and in the rat,
dog, mouse, and rabbit. Furthermore, in vitro studies were performed to elucidate meta-
bolic pathways, elimination and binding to intracellular proteins and plasma proteins. In
the following sections, data on absorption, distribution, metabolism and elimination of tel-
misartan will be discussed.

Absorption
In humans, the extent of absorption was assessed after oral and intravenous adminis-
tration of 40 mg radiolabeled telmisartan. The mean absolute bioavailability of telmisartan
was 43%. In other bioavailability studies, the extent of absorption was between 40%
(40-mg tablet) and 60% at the 160-mg dose level. The absolute bioavailability of the
starting and maintenance dose of 40 mg telmisartan was higher than that of valsartan
(23%) (15), eprosartan (13%) (55), candesartan (15%) (2), and losartan (30%) (32).
Irbesartan, however, displayed a bioavailability of 60 to 80% at the clinically relevant
doses of 75 to 300 mg (7). Telmisartan is not a prodrug and, therefore, does not need to be
converted to an active metabolite (unlike losartan and candesartan) to develop full anti-
hypertensive activity.
In rats, the bioavailability of telmisartan after oral administration was 67%, as deter-
mined by intravenous and oral administration of 1 mg/kg [14C]telmisartan. The com-
pound is subject to saturable, intestinal, first-pass elimination (see section on Plasma
Levels and Pharmacokinetic Parameters).

Distribution
The distribution of telmisartan is determined by its physicochemical properties. As a
highly lipophilic compound (log P = 3.2), it has a high membrane permeability, and be -

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140 W. WIENEN ET AL.

cause telmisartan crosses biological membranes easily, the drug is reversibly bound by
intracellular binding proteins, i.e., glutathione S-transferase (GST), type 1-1 (ligandin) in
hepatocytes. Telmisartan is a weak acid with pK a values of 3.5, 4.1, and 6.0.
Telmisartan distribution was evaluated by whole body autoradiography in rats after in-
travenous and oral administration. The highest levels of radioactivity were detected in the
liver, followed in descending rank order of abundance by kidney, blood and lung.
Twenty-four hours after dosing little activity remained, except in the liver. In the central
nervous system, no radioactivity was detected. In pregnant rats, low levels of radioactivity
were found in the placenta and fetus at Day 21 of gestation, indicating placental transfer of
telmisartan.
Similar to the observations with other AII receptor antagonists, in vitro binding of
telmisartan to plasma proteins, mainly albumin and a1 -acid glycoprotein, was > 98%. In
addition, telmisartan binds to the cytosolic fraction of rat liver homogenates, especially to
GST (ligandin). The affinity of telmisartan was about 5 times higher for the GST fraction
compared with albumin, but was capacity limited (see section on In Vitro Experiments).
Binding of telmisartan to plasma proteins, mainly albumin and a1-acid glycoprotein,
was permissive in all species studied. Permissive plasma protein binding does not restrict
tissue distribution (26), as seen by the high volume of distribution and high plasma
clearance of telmisartan (Table 3). In contrast, restrictive protein binding, visible from a
small volume of distribution of about 0.1 L/kg, might limit drug tissue distribution be-
cause restrictively bound drugs will be confined to the distribution compartment of the
binding protein. The permissive nature of telmisartan plasma protein binding potentially
minimizes the risk of drug interactions caused by protein displacement.
Due to extensive tissue distribution and binding, the volume of distribution (Vss) of
telmisartan was high in all species, ranging from 3 L/kg in dogs to 5 L/kg in rats and to
about 7 L/kg in man. The nonrestrictive nature of telmisartan protein binding and its high
clearance and volume of distribution differentiate telmisartan from other angiotensin an-
tagonists with small volume of distribution of about 0.13–0.24 L/kg, such as candesartan,
valsartan, eprosartan and the active metabolite of losartan. A volume of distribution less
than the volume of free body water amounting to 0.6 L/kg indicates poor transfer and
binding in tissue.

Metabolism
The metabolism of telmisartan was assessed by in vivo/in vitro studies with human and
rat organelles. All results revealed that the biotransformation of telmisartan consisted ex-
clusively of a Phase II reaction, i.e., conjugation to glucuronic acid by UDP-glucuronosyl-
transferases yielding an acylglucuronide of the parent compound. In a pharmacokinetic
and drug metabolism study in man using radiolabeled telmisartan, the plasma concentra-
tion-time profiles of the parent compound and those of total radioactivity were almost
identical for both the oral and intravenous routes of administration. The AUC ratio for
parent compound and total radioactivity was 0.84, suggesting that in man, too, the formed
glucuronide was cleared much more rapidly than the parent compound. Resembling the
findings in animal species, the results of metabolic profiling studies in human plasma re-
vealed the presence of only small amounts of the acylglucuronide of telmisartan (53). In
mice, bile samples contained small amounts of an additional metabolite that was a glyco-
side of the parent compound where telmisartan was conjugated to a hexose sugar. This
metabolite was not observed in any other species, including man.

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In all species investigated, no Phase-I oxidative metabolites were identified, suggesting

that cytochrome P450-dependent isoenzymes are not involved in telmisartan biotransfor-
mation. In rats, it could be shown that after low (1 mg/kg) oral doses the intestinal wall
was the main site of glucuronidation of telmisartan. At higher oral doses, this pathway
becomes saturated due to the limited metabolic capacity of the intestinal UDP-
glucuronosyltransferases.
The functional role of UDP-glucuronosyltransferases was further investigated in Gunn
rats, a strain that is deficient of glucuronosyltransferases of the UGT1 gene family. In
Gunn rats, the rate and extent of telmisartan elimination was much lower than in Wistar
rats, indicating that telmisartan was predominantly glucuronidated by glucuronosyltrans-
ferases of the UGT1 gene family. The glucuronide conjugate of telmisartan was devoid of
any AII receptor antagonist activity.

Excretion
The excretion of telmisartan and its glucuronide was studied by administration of
[14C]labeled compound. Urinary excretion of total radioactivity was low — in the range of
0.1 to 4% — for all species, including man. The majority of the excreted fraction corre-
sponded to telmisartan 1-O-acylglucuronide. In mouse, rat, rabbit, and dog, biliary elimi -
nation into the feces was the predominant route of excretion. Biliary excretion of telmisar-
tan was rapid. In dogs administered [14C]telmisartan, more than 50% of the dose was
recovered in bile within 2 h after dosing. In animal species, nearly complete recovery of
telmisartan was achieved after 48 h. From data on urinary and fecal excretion in a Phase I
study using [14C]telmisartan, the cumulative elimination of radioactivity was calculated.
The excretion-time curves indicated that more than 90% of the dose was recovered within
120 h after either oral or intravenous administration. For either route of administration, re-
covery was essentially complete at 144 h after dosing.

TABLE 3. Species Comparison of Mean Non-Compartmental

Pharmacokinetic Parameters of Telmisartan
Species, Dose
Mouse Rat Rabbit Dog Human
1 mg/kg 1 mg/kg 1 mg/kg 1 mg/kg 40 mg*1
Parameter i.v. Oral i.v.*2 Oral Oral i.v. Oral i.v. Oral
Cmax (ng/mL) 489 162 577 43.5 133 1612.5 51.7 1196 44.7
CL/ f*3 (mL/min/kg) 8.2 12.2 14.6 27 4.9 8.7 49.9 8.4 19.4
t1/2 (h) 7.9 6.8 6.5 11 13 12.8 7.6 19.5 13.8
MRT (h) 9.4 9.6 6.0 17.6 24 5.4 5.2 10.6 17.0
AUC0–¥ (ng × h/mL) 2145 1365 1144 732 3410 1943 334 1132 491
*1 40 mg total dose in humans equivalent to 0.57 mg/ kg in case of a total body weight of 70 kg.
*2 Total radioactivity in blood (ng equivalent). Cmax represents concentration at first measurement
time point (5 min).
*3 In case of i.v. administration: bioavailability f = 1.

Cmax: peak plasma concentration. CL/f: total clearance after oral administration. t 1/2: terminal elimi-
nation half-life. MRT: mean residence time. AUC0–¥: total area under the plasma concentration time
curve.

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142 W. WIENEN ET AL.

In human feces the only component detected was the parent compound, telmisartan,
even after intravenous administration. Based on animal data and in vitro results with
human microsomes and hepatocytes, it appears likely that in man, as in other species, tel-
misartan is excreted in bile as the glucuronide, and that this conjugate is subsequently
cleaved in the intestine by bacterial glucuronidases, liberating the parent compound.

Plasma Levels and Pharmacokinetic Parameters

In humans, C max and, to a lesser extent, AUC increased more than the increment of
dose. The dose proportionality of telmisartan in hypertensive patients was assessed in a
Phase II clinical trial. Doses of 40, 80, and 120 mg telmisartan were taken once daily for
28 days. In the pharmacokinetic analysis, 37 to 38 patients per dose group were included.
The mean C max showed a more than proportional increase with dose, increasing 4.4-fold
for a 2-fold increase in dose from 40 to 80 mg, and 2.4-fold with 1.5-fold increase in dose
from 80 to 120 mg. The mean AUC was nearly proportional with increasing dose, in-
creasing 2.3-fold for a 2-fold increase in dose from 40 to 80 mg and increasing 1.5-fold
with a 1.5-fold increase in dose from 80 to 120 mg (54). The non-linear absorption and
distribution observed with higher doses of telmisartan were considered to be a conse-
quence of saturable, intestinal first-pass metabolism and high affinity, but limited capacity
uptake of telmisartan by the liver.
The saturable first-pass elimination was studied in detail in rats. Telmisartan was ad-
ministered in doses of 1, 10, and 30 mg/kg by the intravenous, intraportal, intravenous,
and intraduodenal (i.d.) routes. Plasma levels of parent compound and glucuronide, and
blood level of total radioactivity were studied. Dose-normalized C max increased 4-fold
with i.v. administration and 7-fold with i.d. administration. The AUC increased 3- and
6-fold, respectively. At the 1 mg/kg dose level, telmisartan is subject to a considerable in-
testinal first-pass effect, resulting in an intestinal extraction ratio of about 0.7. At doses of
10 and 30 mg/kg the first pass was saturated, resulting in extraction ratios of only 0.35
and 0.12, respectively.
Following intravenous administration, the telmisartan plasma clearance of approxi-
mately 8 mL/min/kg was comparable between animal species and humans. The mean res-
idence time ranged from 5 h in dogs to 24 h in rabbits, with values of 11 to 17 h in
humans.
The terminal elimination half-lives in mouse, rat, and dog were in the range of 8 to 10,
6 to 11, and 4 to 15 h, respectively. In man, the average terminal elimination half-life was
generally between 20 and 24 h, contributing to the 24-h antihypertensive efficacy of telmi-
sartan with once-daily dosing.
The half-life of telmisartan was longer than those of other AII antagonists available for
antihypertensive therapy, e.g., valsartan (~7 h) (15), candesartan (9 h) (31), eprosartan
(6 h) (38), the active metabolite of losartan (6 to 9 h) (32) and irbesartan (11 to 15 h) (7).
Because telmisartan trough levels, measured immediately before drug intake, were low,
the drug did not significantly accumulate on once-daily dosing even at high doses of up to
320 mg. The accumulation ratio for the area under the telmisartan plasma concentration-
time curve (AUCss /AUC day 1) was 1.7 after once-daily administration of 120 mg telmisar-
tan for 7 days. Steady state was reached within 3 to 5 days of treatment (Fig. 12).
Concomitant food intake slightly reduced the bioavailability of telmisartan. Forty mg
telmisartan administered with a high-fat, high-caloric breakfast resulted in a 22% decrease
of telmisartan Cmax and an increase of tmax from 1.5 to 2.5 h. At 40 mg telmisartan, the
overall extent of absorption in the fed and fasted state, as judged by AUC, was bioequiva-

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 TELMISARTAN 143

FIG. 12. Mean telmisartan plasma concentration-time curves on Day 1 and Days 6 to 8 of treatment with
telmisartan 20, 40, and 80 mg once daily for 7 days to six mild-to-moderate hypertensive patients.

lent. Moreover, a placebo-controlled study in hypertensive patients confirmed that telmi-

sartan could be administered with or without food without any dose adjustment to reduce
blood pressure effectively.
Female subjects generally had 2- to 3-fold higher plasma levels than male subjects, but
no dose adjustment based on gender is necessary. The pharmacokinetics of telmisartan is
not affected by age. Renal excretion does not contribute to the clearance of telmisartan.
Based on modest experience in patients with mild-to-moderate renal impairment, no
dosage adjustment is necessary in patients with decreased renal function. In subjects un-
dergoing dialysis due to severely impaired renal function, plasma levels of telmisartan
were markedly reduced. The reduction of total telmisartan plasma concentrations was
counteracted by an increase in the free fraction of telmisartan (fraction not bound to
plasma protein). The absolute bioavailability of telmisartan in hepatically impaired sub-
jects was increased to nearly 100%. This could be rationalized by the development of
extrahepatic shunts bypassing the liver and resulting in reduced first-pass hepatic elimi-
nation of telmisartan. Drug elimination of telmisartan in hepatically impaired subjects was
not affected and the terminal elimination half-life remained unchanged.

In Vitro Experiments
Binding studies were performed with the cytosolic fraction of rat liver and with com-
mercially available rat glutathione S-transferase GST, type 1-1 (ligandin) and rat albumin.
Telmisartan has an affinity for GST 1-1 of 5.34 ´ 10–6 M, the binding to albumin being
lower (2.47 ´ 10–5 M). Interestingly, binding of telmisartan to GST 1-1 had no relevant ef-
fects on the glutathione S-transferase activity of GST 1-1.
In vitro biotransformation studies with human hepatocyte cultures showed that the only
metabolite generated was the acylglucuronide of the parent compound. Chromatographic,

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144 W. WIENEN ET AL.

enzymatic and mass spectrometric methods revealed that this metabolite was identical to
the glucuronide isolated from rat bile. Telmisartan was readily glucuronidated in
microsomal preparations from rat liver, kidney and intestine but not in lung microsomes.
Experiments conducted using liver microsomes from hyperbilirubinemic Gunn rats
showed that this rat strain was unable to conjugate telmisartan by glucuronidation. This
observation further substantiated the conclusion that glucuronosyl transferases of the
UGT1 subfamily are primarily involved in telmisartan glucuronidation.
Experiments with isolated, perfused rat livers revealed dose-dependent sequestration of
telmisartan, confirmed glucuronidation as the only metabolic pathway, and demonstrated
rapid biliary excretion of the acylglucuronide.
Telmisartan did not induce or inhibit cytochrome P450 isoenzyme activity, except for
some inhibition of CYP 2C19, which is not clinically relevant, and was not metabolized
via Phase I reactions. Therefore, the potential risk of drug interactions with compounds
subject to CYP450-dependent biotransformation is low.
There is a wealth of information on immunologically based, clinically relevant adverse
reactions to several drugs that are probably related to the formation of highly reactive
acylglucuronides (6). Therefore, the reactivity of the telmisartan acylglucuronide with al-
bumin was compared with that of a series of other drugs (tolmetin, zomepirac, diflunisal,
and diclofenac). Telmisartan and diclofenac were studied in detail under identical, physio-
logically relevant conditions. Telmisartan 1-O-acylglucuronide had an apparent half-life
of 26.2 h compared with 0.5 h for diclofenac. This stability is most likely attributed to the
steric hindrance of the carboxylic function in telmisartan. Furthermore, it was shown in
rats that the 1-O-acylglucuronide was very rapidly cleared, indicating low systemic ex-
posure to this metabolite. The potential risk of adverse reaction due to covalent protein ad-
ducts is, therefore, considered to be very low (12).

Conclusion
The pharmacokinetics of telmisartan is governed by its high lipophilicity and high
membrane permeability, binding to plasma proteins and to GST, type 1-1 (ligandin) in the
liver. The plasma protein binding is high, about 98%, but not restrictive as is indicated by
the high volume of distribution and rapid plasma clearance. Telmisartan is not a prodrug
and has a long terminal elimination half-life of approximately 24 h, making it ideal for
once-daily dosing. Telmisartan does not significantly accumulate on multiple dosing. The
compound is metabolized exclusively by conjugation with glucuronic acid. After oral ad-
ministration, first-pass glucuronidation of telmisartan occurs in the intestinal wall. The
pharmacodynamically inactive acylglucuronide is very stable and rapidly cleared by bili-
ary excretion. The absolute bioavailability in humans is between 40% (40 mg dose) and
60% (160 mg dose). Telmisartan did not induce or significantly inhibit cytochrome P450
isoenzyme activity and was itself not metabolized by Phase I reactions. Therefore, the po-
tential risk of drug interactions with compounds subject to CYP450-dependent biotrans-
formation is low.

TOXICOLOGY
Special Safety Pharmacology
Telmisartan showed low acute toxicity during cumulative infusion into anesthetized
guinea pigs, with lethal doses ranging from 193 to 247 mg/kg. The potential effect of tel-

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 TELMISARTAN 145

misartan on the central nervous system was studied in rats and mice. At 30 mg/kg p.o.,
telmisartan did not influence spontaneous motor activity in conscious, freely moving rats
or hexobarbital-induced sleeping time in rats. It also failed to cause muscle relaxation in
mice at an oral dose of 30 mg/kg. These findings suggest that telmisartan shows low po-
tential to act on the CNS and that there is no effect on hepatic drug-metabolizing enzymes.
No significant effects were observed on gastric emptying and on intestinal propulsion
after administration of doses of 10 and 30 mg/kg p.o. in rats, suggesting that telmisartan
has no effect on gastrointestinal motility (Data on file, Boehringer Ingelheim).
Injection of AII (1 nmol/kg) in anesthetized rats led to a transient fall in gastric arterial
conductance, while femoral conductance was not altered. Telmisartan (1 mg/kg i.v.) sig -
nificantly increased vascular conductance only in the gastric arterial bed and inhibited the
constrictor response to AII. Vasopressin-induced constriction of either arterial bed was not
influenced by telmisartan. These data indicate that telmisartan dilates the gastric arterial
bed of the rat, and point to a constrictor role of endogenous AII in the gastric vasculature
(25,57).

Single-Dose Studies
The acute toxicity of telmisartan was assessed in Chbb:THOM rats by the oral and in-
travenous routes, and in Beagle dogs by the oral route. The oral toxicity was low the
maximum dose administered, 2000 mg/kg, was well tolerated in both species.
In rats, the LD 50 of telmisartan after intravenous injection was between 150 and
250 mg/kg. Clinical signs of toxicity appeared immediately after dosing, and included sa-
livation, sedation, prone or lateral position, ptosis, hypopnea, and cyanosis. All animals
given 150 mg/kg recovered within 4 h after dosing. At doses of 200 mg/kg and higher,
peripheral vasodilatation and tonic-clonic convulsions were observed. Most deaths oc-
curred within 24 h after dosing and were attributed to circulatory collapse due to marked
hypotensive activity.

Repeated-Dose Studies
Telmisartan was administered by gavage to Chbb:THOM rats for 1, 3, and 6 months at
daily doses ranging between 0.1 and 500 mg/kg and to Beagle dogs for 1, 3, and 12
months at daily doses between 5 and 500 mg/kg. In addition, intravenous studies with
doses of 0.1, 2, and 20 mg/kg/d in rats and 0.5, 5, and 50 mg/kg/d in dogs were per-
formed with an administration period of 4 weeks. The principal side effects observed after
both oral and intravenous dosing in either species were directly or indirectly linked to
telmisartan’s mode of action — specific blockade of the AT1 receptor — and followed a
pattern known from preclinical studies with ACE inhibitors and recently described also
for other AT 1 receptor antagonists (1,10,16–24,27,41,45). Side effects included gastric
and/or duodenal mucosal erosions and ulcers, accompanied by slight to mild increases in
white blood cell counts in rats at doses of ³ 4 mg/kg orally or ³ 2 mg/kg i.v., and in dogs
at ³ 40 mg/kg. No-effect exposure levels for gastrointestinal toxicity were lower in rats
than in dogs, and male rats tended to develop more severe lesions at a higher incidence.
However, no gastric mucosal damage was observed in a carcinogenicity study in mice
when telmisartan doses of up to 1000 mg/kg/d were given for 2 years.
The possibility of a direct irritant effect of telmisartan has been excluded, since gastric
lesions were also observed after intravenous dosing. In additional studies, it was deter-
mined that gastric lesions were not caused by reduced gastric mucosal blood flow or in-

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146 W. WIENEN ET AL.

creased gastrin levels, and that they could be prevented by oral saline supplementation.
However, no definitive pathogenesis was identified.
In comparative studies at pharmacodynamically equipotent doses, telmisartan and
losartan had similar ulcerogenic potential in rats, while lisinopril caused more severe
damage to the gastric mucosa. Furthermore, it was shown that the rats used in the telmisar-
tan studies (Wistar-derived Chbb:THOM rats) were more prone to gastric side effects than
the Sprague–Dawley strain that has been used in most ACE-inhibitor studies. The low in-
cidence of gastrointestinal side effects observed with ACE inhibitors and telmisartan in
therapeutic use suggested that the ulcerogenicity observed in normotensive experimental
animals does not translate into increased risk in hypertensive patients.
Hypertrophy of the juxtaglomerular apparatus (JGA) and increased granularity of
renin-producing cells of the JGA, afferent arterioles and interlobular arteries of the kidney
are a well-documented consequence of blockade of the renin-angiotensin–aldosterone
system (RAAS), and are not judged to pose a risk to patients receiving drugs of these
classes (9,10, 24,27,33,45). They were observed in rats at doses of ³ 1 mg/kg and in dogs
at ³ 5 mg/kg.
Other effects were: reversible, slight to mild (~10–46%), stable increases in serum po-
tassium levels, attributable to AII antagonism which suppresses aldosterone (48) minimal
to mild, reversible increases in urea nitrogen (BUN) and creatinine; slight to mild, re-
versible reductions in erythrocyte, hematocrit and/or hemoglobin values in the absence of
microscopically detectable bone marrow changes, attributable to blockade of angiotensin
II-stimulated erythropoietin production (23,30) and a pronounced and persistent reduction
in body weight gain with resulting reduced liver weights, slightly elevated values for
ALT and AST, and increased bilirubin values. The latter effects are considered to be due
to partial saturation of UDP-glucuronyltransferases by high doses of telmisartan because
enzymes of the same UDP-glucuronyltransferase family (UGT1) metabolize both telmi-
sartan and bilirubin.
Despite profound and persistent (³ 24 h) blood pressure reductions in normotensive
animals, no drug-induced ECG abnormalities or arrhythmogenic potential were noted at
repeated doses up to 500 mg/kg for 26 (rat) or 52 (dog) weeks. Reversible, dose-de-
pendent reduction in heart weight, a potentially beneficial effect of telmisartan, was con-
sistently observed after oral or i.v. administration in the rat. The dog was less sensitive to
this change, requiring a longer exposure period.
Concomitant toxicokinetic examinations showed that the therapeutic index at the
lowest no-effect level in the oral studies in dogs (4.7) and rats (0.32) was small or absent.
Despite this finding, telmisartan causes relatively few side effects in human patients
treated for hypertension. Results of repeated dose-toxicity studies in the dog and rat
appear to overestimate adverse events both qualitatively and quantitatively. Virtually all
toxic effects of telmisartan were linked to its mechanism of action. Therefore, the limited
reproducibility of adverse events in humans can be most logically attributed to disruption
of RAAS homeostasis in the normotensive models used in toxicology experiments, as op-
posed to improvement or normalization of this system in hypertensive patients.

Reprotoxicity
The effect of telmisartan on fertility and early embryonic development was assessed in
sexually mature male and female Chbb:THOM rats at oral doses of 5, 15, and 100 mg/kg.
Administration started in males 28 days and in females 14 days before mating, and con-
tinued through mating until Day 6 of pregnancy. Cesarian section and necropsy of females

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 TELMISARTAN 147

were performed on Days 14 to 16 of pregnancy. Fertility and reproductive performance

were not impaired by drug exposure up to the maximum dose of 100 mg/kg.
To assess effects on embryonic development, telmisartan was administered to pregnant
Chbb:THOM rats and Chbb:HM rabbits at oral doses of 5, 15, and 50 mg/kg and 5, 15,
and 45 mg/kg from Days 7 to 16 and 6 to 18 of pregnancy, respectively. As pregnant
rabbits showed high sensitivity to telmisartan, an effect reported with other drugs acting
on the RAAS (40), the teratogenicity study was conducted with saline supplementation.
Rats were subjected to hysterectomy on gestation day (GD) 21, or allowed to litter natu-
rally and raise their young through weaning at the age of 21 days. All rabbits were sub-
jected to hysterectomy on Day 29. In a separate pharmacokinetic study, telmisartan could
be detected in the placenta, fetus and amniotic fluid of rats after single oral doses of
1 mg/kg on GD 12 and 18, leading to the assumption that the embryo/fetus is exposed to
telmisartan during the critical period of organogenesis. All rats survived to the termination
of the study and litter parameters in the hysterectomy and littering groups were compa-
rable between study groups. At the high dose used in the rabbit study (45 mg/kg),
maternal toxicity, including death in 1/16 does, reduced body weight gain and food
consumption were observed, leading to total resorptions in 5/16 animals. Furthermore,
resorption rate was significantly increased in this group. In the two lower-dose groups,
litter parameters were not significantly different from control values. No teratogenic po-
tential was observed in any group of either study. Reflexes, developmental functions and
body weight developed normally in the rat littering groups. It was concluded that the
NOEL for teratogenicity and embryotoxicity was above 50 mg/kg with mean maternal
AUC0–6 h of 24–1 mg × h/ml in rats, and 15 mg/kg with resulting mean AUC 0–7 h of
37.5 mg × h/ml in rabbits.
The peri/postnatal toxicity of telmisartan was investigated in Chbb:THOM rats at oral
doses of 5, 15, and 50 mg/kg from Day 6 of gestation until postnatal Day 21. All dams
survived the study without clinical signs. However, body weight development at 15 and
50 mg/kg was significantly reduced. Litter parameters did not differ significantly between
groups. Viability rate of the offspring was decreased in the 15 and 50 mg/kg groups. Al-
though the difference was not statistically significant, it was considered to be caused by
the administration of telmisartan, as the values were clearly outside the historical range.
Furthermore, birth weight of the newborn pups at 50 mg/kg was significantly reduced but
normalized during the remaining study period. Apart from a slight delay in eye opening,
no group differences were observed in maturation indices, reflexes and sensory functions,
behavior, fertility and fecundity of the progeny. The maximum no-toxicity dose for dams
and peri/postnatal development was 5 mg/kg, with a resulting mean AUC level of
1.2 mg × h/ml in pregnant rats.
Although reprotoxicity studies in animals showed that telmisartan poses no risk to em-
bryos and fetuses at therapeutic dose levels, clinical experience with ACE inhibitors has
shown increased risk of fetal and neonatal toxicity and death (“ACE inhibitor fetopathy”)
when women are exposed to RAAS-active drugs during the last two trimesters of preg-
nancy (3), an effect that could not be reproduced in animal models (3,8,11,16–20,52).
Since this may be a class effect of drugs acting on the RAAS, telmisartan is contraindi-
cated during pregnancy. Telmisartan is excreted in milk when it was administered to lac-
tating rats at a single oral dose of 1 mg/kg, concentrations in milk were 1.5- to 2-fold
higher than that in maternal plasma and were detectable over 48 h post-dose.

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148 W. WIENEN ET AL.

Genotoxicity
Telmisartan produced no evidence of mutagenic potential in in vitro studies in the
Ames test and in the HPRT test in Chinese hamster V79 cells. A slightly increased chro-
mosomal aberration frequency in an in vitro chromosomal aberration assay in human lym-
phocytes was observed only at a highly cytotoxic concentration, and was therefore con-
sidered to be due to non-specific toxic effects on the test system rather than a clastogenic
potential of the test substance. This conclusion was supported by the results of an in vivo
experiment in the mouse micronucleus assay, in which there was no evidence of telmisar-
tan-related mutagenicity.

Carcinogenicity
Carcinogenicity studies were performed by dietary administration of telmisartan at
maximum tolerated doses of 10, 100, and 1000 mg/kg to Crl:CD-1 mice and of 10, 100,
and 1000 mg/kg to Chbb:THOM rats over a period of 104 weeks. At these doses, ex-
posure levels exceeded human exposure levels at the maximum clinical dose of 80 mg/d
by factors of 121 to 205 and 75 to 116, respectively. The studies revealed no evidence sug-
gestive of carcinogenic hazard for humans.

CLINICAL EXPERIENCE

Placebo-Controlled Studies
The antihypertensive activity of telmisartan was demonstrated in 6 fixed-dose, pla-
cebo-controlled clinical trials that included 1146 patients treated with telmisartan. Blood
pressure was reduced after the first dose of telmisartan and there was a gradual increase in
the antihypertensive effect during continued treatment for up to 12 weeks, with most of
the increase occurring during the first month (Data on file, Boehringer Ingelheim). The
magnitude of blood pressure reduction from baseline averaged 10.6 mm Hg for systolic
and 8.7 mm Hg for diastolic blood pressure after telmisartan 40 mg/d, and 13.3 for sys-
tolic and 9.8 mm Hg for diastolic blood pressure after telmisartan 80 mg/d.
Results of three placebo-controlled, dose-response studies demonstrate that telmisartan
given at doses of 20, 40, 80, 120, and 160 mg/d for 4 to 12 weeks is more effective than
placebo in lowering diastolic and systolic blood pressure (14,44,51). However, in the
study that directly compared all five doses of telmisartan, doses of ³ 40 mg reduced
supine systolic blood pressure significantly more effectively than the 20 mg dose. Trough:
peak ratios of > 80% were consistently seen with doses of 40 mg and 80 mg of telmisartan
in placebo-controlled clinical studies (39).

Duration of Blood Pressure Control

The ambulatory blood pressure profile of telmisartan was compared with that of the
prototype AII antagonist, losartan, in a randomized, double-dummy, double-blind, com-
parative and placebo-controlled trial in patients with mild-to-moderate hypertension (34).
The primary endpoint was the change from baseline in ambulatory diastolic blood
pressure over the 18 to 24 h post-dose period, comparing telmisartan 80 mg vs. losartan
50 mg, and telmisartan 40 mg vs. losartan 50 mg. Both telmisartan 40 mg and 80 mg were

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 TELMISARTAN 149

FIG. 13. Mean changes in ambulatory blood pressure from baseline at Week 6 with telmisartan and losartan: 18-
to 24-h post-dosing (A) and 24-h mean (B). From ref. 34.

shown to be significantly more effective than losartan in reducing blood pressure during
the 18 to 24-h post-dose period, and both telmisartan doses were significantly more ef-
fective than losartan 50 mg in reducing the 24-h mean systolic and diastolic blood pres-
sures (Fig. 13).
In a double-blind, randomized, placebo- and active-controlled study of 232 patients
with mild-to-moderate hypertension, telmisartan was compared with the calcium antag-
onist, amlodipine, using both conventional clinic and ambulatory blood pressure measure-

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150 W. WIENEN ET AL.

FIG. 14. Efficacy of telmisartan and amlodipine during 24-h ambulatory blood pressure monitoring in patients
with mild-to-moderate hypertension. From ref. 29.

ments (ABPMs) during 12 weeks of treatment (29). Both telmisartan (40 to 120 mg) and
amlodipine (5 to 10 mg) produced similar significant decreases in office cuff supine sys-
tolic and diastolic blood pressures compared with placebo. However, diastolic blood
pressure reductions at night and during the early morning hours were significantly greater
with telmisartan (Fig. 14), and across the dosing period there was a trend towards a greater
reduction with telmisartan than with amlodipine. In addition, a 24-h mean ambulatory dia-
stolic blood pressure measurement < 85 mm Hg was observed in 71% of telmisartan pa-
tients, compared with only 55% of those treated with amlodipine. Ambulatory blood
pressure findings support the view that the antihypertensive effect of telmisartan persists
constantly over 24 h after dosing and includes the last 4 h before the next dose (39).

Efficacy vs. Other Antihypertensives

The antihypertensive efficacy of telmisartan was compared with that of the ACE in-
hibitor, enalapril, at a dose of 20 mg/d, in a 12-week study of patients with mild-to-mod-
erate hypertension (51). Both doses of telmisartan produced numerically greater reduc-
tions in blood pressure than did enalapril, and both drugs produced statistically significant
reductions in blood pressure compared with placebo, indicating effective blood pressure
control with once-daily dosing (Fig. 15). The percentage of responders (³ 10 mm Hg re -
duction in diastolic pressure and/or trough blood pressure £ 90 mm Hg) was higher with
both telmisartan 40 mg/d (57%) and 80 mg/d (61%) than with enalapril (44%).
A placebo-controlled, randomized, parallel-group study of patients with mild-to- mod-
erate hypertension compared telmisartan 40 mg (uptitration to 80 mg), telmisartan 80 mg
(uptitration to 120 mg), atenolol 50 mg (uptitration to 100 mg) or placebo once daily for 8
weeks. Both telmisartan regimens were significantly superior to placebo in reducing
supine diastolic and systolic blood pressures however, there were no significant differ-
ences between telmisartan doses or between the telmisartan regimens and atenolol (14).

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 TELMISARTAN 151

FIG. 15. Change from baseline in systolic and diastolic blood pressure after 12-week treatment with placebo,
telmisartan 40 or 80 mg/d, or enalapril 20 mg/d. Adapted from ref. 51.

Efficacy in Elderly Patients

The efficacy of telmisartan in elderly patients was investigated in a randomized,
double-blind, active-controlled parallel group study of patients with mild-to-moderate hy-
pertension. Results showed that doses of 20 to 80 mg telmisartan once daily (with or
without addition of hydrochlorothiazide) reduced blood pressure as effectively as oral
doses of 5 to 20 mg enalapril once daily (with or without hydrochlorothiazide) (28). In ad-
dition, subgroup analyses of additional controlled studies showed no relevant difference in
mean blood pressure changes between elderly and younger patients.

SUMMARY
Telmisartan is a potent, insurmountable AII receptor antagonist that shows high speci-
ficity for the AT1 receptor subtype. Among the AII receptor antagonists, telmisartan ex-
hibits the highest partition coefficient, reflecting high lipophilicity and extensive pene-
tration into target tissues and organs. In clinical studies in hypertensive patients,
telmisartan was shown to reduce blood pressure more effectively than the AII-receptor an-

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152 W. WIENEN ET AL.

tagonist, losartan, and lowered blood pressure to the same extent as members of other
major antihypertensive drug classes, such as ACE inhibitors, b-receptor blocking agents
and calcium antagonists. In common with other sartans, telmisartan offers placebo-like
safety and tolerability in hypertensive patients. Telmisartan’s pharmacologic profile, in-
cluding a long elimination half-life, results in an excellent trough:peak ratio and sustained
control of blood pressure throughout the once-daily dosing interval.

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