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DIFFERENTIATING ANTIHISTAMINE EFFICACY FROM POTENCY*
—
Scott A. Waldman, MD, PhD
ABSTRACT
The ideal antihistamine would optimize both
receptor and clinical pharmacology, combining
high receptor affinity, reflected by high potency,
with outstanding clinical efficacy. Because the
basic concepts of potency and efficacy are often
confused and used interchangeably within the scientific and pharmaceutical industry, the distinction
between these 2 terms must be understood in order
for them to be used within the correct context. This
article defines potency and efficacy and discusses
how these terms are applied to current studies in
antihistamine therapy.
Since their discovery in the 1930s, histamine-1
(H1)-receptor antagonists that are therapeutically classified as antihistamines have been widely used in the
treatment of allergic disorders. During this time, many
antihistamines have been developed to have distinct
pharmacologic profiles, with the aim of offering optimal efficacy with few, if any, side effects. Therefore, a
significant amount of research has been directed at
developing new antihistamines that have greater
potency and clinical efficacy compared with those that
are already available. As such, antihistamines provide
good examples when examining the relationship
between measures of potency and clinical efficacy.
(Advanced Studies in Medicine. 2002;2(24):877-881)
POTENCY MEASUREMENTS
n basic pharmaceutical development, the ideal
drug would be designed to optimize both receptor
and clinical pharmacology, combining high receptor potency with excellent clinical efficacy and a
good safety profile. However, within the scientific
and pharmaceutical industries, the pharmacologic concepts of potency and clinical efficacy are often confused
and used interchangeably.
I
*Based on a presentation given by Dr Waldman at the
XXI Congress of the European Academy of Allergology and
Clinical Immunology.
Address correspondence to: Dr Scott A. Waldman,
Samuel MV Hamilton Family Chair in Medicine, Dept of
Medicine & Biochemistry and Molecular Pharmacology,
Thomas Jefferson University, 132 South 10th Street, 1170
Main, Philadelphia, PA 19107-5563.
Advanced Studies in Medicine
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Potency is a basic expression of drug activity in
terms of the concentration or amount required to produce a predefined pharmacologic effect. Potency assays
are commonly used as initial screens during drug
development, and the receptor potency of a new compound can often be a key factor in its progression
through the development process.
The potency of a drug can be measured under a
variety of strictly controlled in vitro and in vivo conditions. Under in vitro conditions, the potency of an
antihistamine reflects its ability to competitively
antagonize histamine at H1-receptors; it reflects the
affinity of the compound for H1-receptors. One of the
simplest and most commonly used assays to measure
the potency of a compound is the competition radioligand binding assay, in which the potency of an antihistamine is quantified based on its ability to block the
binding of a specific radiolabeled ligand to H1-receptors. This type of assay has been used to demonstrate
that desloratadine exhibits a potency at H1-receptors
that is comparable to astemizole but is 15 times more
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potent than its parent molecule, loratadine. 1
However, an important consideration is that the relative potency of a compound will depend on the
particular assay system and tissue type used. For
example, the rank order of potency of various antihistamines in a calcium ion (Ca2+) flux assay, using
Chinese hamster ovary cells transfected with H1receptors, indicated that desloratadine was more
potent than chlorpheniramine.2 In contrast, comparing the potency of the same antihistamines by their
ability to antagonize histamine-induced contractions
of guinea pig ileum showed that chlorpheniramine
was 30 times more potent than desloratadine.1 This
exemplifies that in vitro potency data may vary
depending on the type of assay, the conditions used,
and the tissue in which potency is measured.
In vivo, the potency of antihistamines reflects the
relationship between dose or concentration and a targeted pathophysiologic response. For example, a popular in vivo test for antihistamine potency is the
epicutaneous histamine-induced wheal and flare assay.
This test assesses the potential for clinical effectiveness
by measuring in vivo potency at peripheral receptors.
It relies on the ability of epicutaneously injected histamine to bring about the wheal and flare, a neurovascular response that involves reflex vasodilation (flare)
and local swelling caused by plasma extravasation
(wheal). In this assay, the potency of an antihistamine
is judged by the degree with which it suppresses the
wheal and flare response. A recent wheal and flare
study in healthy adult volunteers demonstrated that
fexofenadine was more effective at fully inhibiting the
wheal and flare responses compared with both loratadine and desloratadine, with a faster onset of action.3
Interestingly, desloratadine was not as effective at
inhibiting the wheal response compared with loratadine, which is in contrast to earlier radioligand binding studies using cellular membranes where
desloratadine was found to be 15 times more potent
than loratadine.1 Similarly, although the radioligand
binding profiles of the antihistamines astemizole,
chlorpheniramine, cetirizine, and terfenadine show
that astemizole and chlorpheniramine are more potent
than cetirizine and terfenadine, the results of the histamine-induced wheal and flare assay show that cetirizine, at regular dosing, and terfenadine, at double
dosing, are more potent than astemizole and chlorpheniramine (Figure 1).4 Thus, when using potency
data to differentiate between drugs, both the endpoint
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selected for measurement and the protocol used must
be taken into consideration.
DOES POTENCY REFLECT CLINICAL EFFICACY?
Many examples of discrepancy can be found
between antihistamine potency and clinical efficacy.
For example, although loratadine and fexofenadine
have been demonstrated to have equal H1-receptor
potency,2 a large randomized, double-blind clinical
study found that fexofenadine was significantly better
than loratadine in relieving eye symptoms and nasal
congestion in patients with seasonal allergic rhinitis
(P ≤ .05).5
In pharmaceutical development, the in vitro and in
vivo potency of the drug candidate is only one of the
factors involved when considering whether to progress
the drug into clinical trials. Clinical efficacy measures
the magnitude (quantity) and profile (quality) of clinical disease improvement following drug administration in human populations. The ability of a drug to
interact with effector systems in humans is influenced
by pharmacokinetic parameters, such as absorption
and metabolism, which determine the bioavailability
of the drug at sites of action in the body. The clinical
usefulness of a drug may be limited by undesired
adverse effects and by interactions at sites other than
target receptors that may or may not be characterized.
Thus, in contrast to potency, which quantifies a single
endpoint in relation to drug dose or concentration,
clinical efficacy measures the therapeutic benefit
brought about by the integration of complex interactions among various tissues, receptors, effector mechanisms, and physiologic processes.
PHARMACOKINETIC AND PHARMACODYNAMIC FACTORS
The potency of a drug is evaluated by assessing the
response to the direct application or administration of
the drug to a particular tissue under strictly defined
conditions. Therefore, it does not take into account
the extent to which a drug reaches its sites of action;
that is, the bioavailability of the drug at the target
organ. The molecular size, shape, and solubility of a
drug are key factors determining bioavailability, as
these properties affect the distribution of the drug
around the body. Accordingly, an effective drug will
easily penetrate its site of action, increasing the
bioavailability of the drug to its target receptors. A
recent study of healthy volunteers found that, com-
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pared with an equivalent dose of diphenhydramine,
fexofenadine penetrated the skin to a greater extent.
The clinical relevance of this was reflected in the significantly greater suppression of both wheals and flares
by fexofenadine following epicutaneous injection of
histamine into the skin.6
trate this point, although cetirizine has an apparently
greater ability to inhibit histamine-induced wheal and
flare responses compared with loratadine, nasal challenge studies have failed to show any difference in efficacy between cetirizine and loratadine.7 Whereas it is
clear that histamine is the primary mediator in pruritus and sneezing, other agents such as neuropeptides,
sulfidopeptide leukotrienes, or even prostaglandin D2
may contribute to other symptoms such as rhinorrhea
and nasal congestion.
Furthermore, while antihistamines clearly exert
their main pharmacologic effects by competitive
antagonism of histamine for H1-receptors present in
smooth muscles, nerve endings, and glandular cells,
some of the newer antihistamines, such as cetirizine,
loratadine, desloratadine, and fexofenadine, also
exhibit significant anti-inflammatory effects. As an
example, fexofenadine has been shown to significantly reduce the release of numerous late-phase
inflammatory mediators and adhesion molecules
such as granulocyte macrophage-colony stimulating
DIFFERENCES IN TARGET ORGAN CELLULAR MECHANISMS
The comparative ability, or potency, of various
antihistamines to block histamine-induced wheal and
flare in the skin has often been used to predict the
global antiallergic clinical efficacy of various antihistamines in allergic rhinitis. However, the allergic
response is not simply the consequence of one mediator, but results from a complex cascade of interactions
among specialized cells and mediators. Thus, an
important point to note is that unlike the clinical situation, the histamine-induced wheal and flare reaction
involves neither mast cell degranulation nor activation
of the complex cascade of cellular events that are
observed in the late-phase allergic response. To illus-
Figure 1. Comparison of Effects of Antihistamines in Receptor Binding Assays and Histamine-Induced Wheal and
Flare Assays
Astemizole
Chlorpheniramine
>
Cetirizine 10 mg
Terfenadine 120 mg
Cetirizine
Terfenadine
Chlorpheniramine,
Astemizole
80
Cetirizine,
Terfenadine
60
50
40
20
Mean Wheal Area (cm2)
Receptor Occupancy (%)
100
>
Astemizole 10 mg
Chlorpheniramine 4 mg
Placebo
Astemizole
Cetirizine
0.2
Terfenadine
Chlorpheniramine
0.1
0
0
log [Antihistamine]
0
0.5
1 2
3 4
5 6 7 8
9 10 11 12 24
Time (h)
Modified with permission from: Simons FE, McMillan JL, Simons KJ. A double-blind, single-dose, crossover comparison of cetirizine, terfenadine, loratadine, astemizole,
and chlorpheniramine versus placebo: suppressive effects on histamine-induced wheals and flares during 24 hours in normal subjects. J Allergy Clin Immunol.
1990;86(suppl 4, pt 1):540-547.
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factor, soluble intracellular adhesion molecule 1,
interleukin-8, and leukotriene-C4.8 These additional
anti-inflammatory effects cannot be explained purely on the basis of classic H1-receptor blockade and
therefore cannot be predicted from the results of
potency measurements. The clinical significance of
these effects is currently unknown.
TARGET ORGAN SELECTIVITY
In addition to receptor selectivity, the ideal
drug will only affect its target sites of action. The
first-generation antihistamines are small, lipophilic
molecules, which enables them to easily cross the
blood-brain barrier and bind to central H1-recep-
880
P<.001
AMP = adenosine monophosphate; CHO = Chinese hamster ovary.
Adapted from: Ellis J, Seidenberg M. Desloratadine interacts with muscarinic
acetylcholine receptors with high affinity and antagonizes the cyclic AMP
response at the M2 subtype. J Allergy Clin Immunol. 2001;107(2):S160.
Figure 3. Effect of Desloratadine on Heart Rate in
Conscious Dogs
Heart Rate (% change from control)
RECEPTOR SELECTIVITY
Only a few drugs can be said to be fully selective
for their target receptor, and often they possess additional pharmacologic effects. In some cases, such as
the anti-inflammatory effects described above, these
additional effects can be beneficial. However, nonselective effects are often unwanted, and are related to
the drug’s affinity for nontarget receptors. For example, the H1-receptor shares close sequence homology
with muscarinic acetylcholine M2-receptors, and
many of the first-generation antihistamines, such as
hydroxylamine and promethazine, possess a high
affinity for both H1-receptors and the muscarinic
receptors M1, M2, and M3. Antagonism of M2receptors by nonselective antihistamines can result
in adverse effects since M2-receptors are involved
in maintaining vagal tone, and blockade of these
receptors causes an increase in heart rate.9 Recent
experiments have shown that the antihistamine
desloratadine exhibits a high affinity for cardiac
M2-receptors; it is 5 times more selective for H1receptors compared with M2-receptors.10 This
study also showed that desloratadine was able to
antagonize the effects of the muscarinic agonist,
carbachol, on the inhibition of adenyl cyclase
(Figure 2). In contrast, the selectivity ratio of fexofenadine for these 2 receptors is 2 orders of
magnitude higher: fexofenadine is 600-fold more
selective for H1-receptors compared with M2receptors.10 Moreover, in a recent study, the
antimuscarinic effect of desloratadine was shown
to increase the resting heart rate of conscious
dogs both under normal conditions and following heart failure (Figures 2 and 3).11
Figure 2. Effects of Desloratadine (DCL) and
Fexofenadine (FEX) on Cyclic AMP Levels in CHO
Cells Expressing M2 Muscarinic Receptors
Adapted from: Igawa A, Cheg CP, Little W. Desloratadine, but not fexofenadine,
increases the heart rate in dogs before and after heart failure. Allergy. 2001;56(suppl
68):203-204.
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tors. Indeed, positron-emission tomography studies
demonstrate a strong positive correlation between the
degree of central H1-receptor binding and the level of
sedation caused by some antihistamines.12 The high
levels of sedation and subsequent performance deficits
seen with the first-generation antihistamines led to the
development of new lipophobic H1-receptor antagonists, which do not cross into the central nervous system.13 This lack of central effects means that,
compared with their forerunners, the newer antihistamines are more clinically useful in the practical daily
treatment of common allergies.
CONCLUSION
Although potency is often mistakenly equated with
efficacy, drugs with greater potency do not necessarily
have greater clinical efficacy, as therapeutic behavior is
modulated by pharmacokinetic and pharmacodynamic parameters, and by further interactions at sites other
than the target receptor, which may or may not be
characterized. This is exemplified in the case of antihistamines by studies demonstrating that agents with a
similar potency may differ dramatically in clinical efficacy. Potency is certainly a useful marker of the potential therapeutic actions of a drug at the preliminary
stages of drug development, but beyond this stage,
clinical efficacy can only be assessed within the patient
population. Moreover, relative potency has been
shown to vary across various investigative models.
Taken together, these observations emphasize the
importance of clearly distinguishing between potency
and efficacy when analyzing the results of clinical outcomes of studies comparing drugs in a particular therapeutic class, such as antihistamines.
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