Download the concept of the therapeutic window in the choice of h1

PROCEEDINGS
THE CONCEPT OF THE THERAPEUTIC WINDOW
IN THE CHOICE OF H1-RECEPTOR ANTAGONIST*
—
Peter H. Howarth, DM, FRCP†
ABSTRACT
Antihistamines have existed for more than 60
years. The first-generation antihistamines provided
symptom relief from allergic rhinitis but were also
associated with undesired side effects due to lack of
receptor selectivity and central nervous system penetration. Since then, newer-generation antihistamines have been specifically developed to reduce
the occurrence of side effects while still providing
efficacy. Differences of cardiotoxicity and sedation
still exist, however, among available antihistamines.
The choice of available antihistamines, therefore, is
best informed through evaluation of the therapeutic
window of each medication—ie, the dose range
over which a drug is efficacious while being free
from side effects. A broad therapeutic window conveys the most ideal characteristics. The therapeutic
window provides considerably more information
for clinical considerations than standard individual
terms, such as potency, efficacy, or safety, combining these characteristics into an easily attainable
understanding of the agent. This paper describes
the importance of conscientious choices of antihistamines through the use of a therapeutic window
based on recent research. Understanding the therapeutic windows of these agents will enable physicians to make informed treatment decisions based
on the requirements of the patient and characteristics of the antihistamine.
(Adv Stud Med. 2004;4(7A):S508-S512)
*Based on a presentation given by Prof Howarth at the
2003 World Allergy Organization Congress.
†Reader in Medicine and Honorary Consultant Physician,
Respiratory Cell and Molecular Biology, Southampton General
Hospital, Southampton, United Kingdom.
Address correspondence to: Peter H. Howarth, DM, FRCP,
Respiratory Cell and Molecular Biology, Mail point 810,
Southampton General Hospital, Tremona Road, Southampton,
UK SO16 6YD. E-mail: [email protected].
S508
ore than 6 decades have passed since
the first antihistamines were developed and used to treat allergic disease.
These initial H1-receptor antagonists,
although effective in the treatment of
urticaria and rhinitis, were shown to cause undesired side
effects, such as sedation, due to central nervous system
(CNS) penetration. They also were shown to cause a
range of other effects due to lack of receptor specificity.
In the late 1970s and early 1980s, second-generation
antihistamines, such as terfenadine, cetirizine, and
loratadine, were developed to improve receptor specificity and reduce the sedative properties. Additional antihistamines, such as fexofenadine, intranasal levocabastine,
and intranasal azelastine, were also developed to further
improve the safety profile. Other H1 antihistamines have
also been developed, including mizolastine, desloratadine, and levocetirizine. Despite the range of antihistamines available, sedation and cardiotoxicity remain as
potential undesirable side effects of some presently prescribed drugs.
Given the wide range of H1 antihistamines, physicians must assess these deleterious effects as well as the
efficacy of the specific therapy to make an educated
choice regarding medication. This choice is best
informed through evaluation of the therapeutic window for each medication.
M
THERAPEUTIC WINDOW
The therapeutic window of an H1-receptor antagonist is the dose range over which it is efficacious and also
free from unwanted side effects (Figure 1). The positioning of the clinically recommended dose (range) within
this window provides an easy understanding of the
impact of the interactions that decrease or increase therapeutic bioavailability as well as the impact of dose
adjustments on both safety and efficacy. The lower limit
of the therapeutic window is set by the lowest clinically
effective dose for the disease condition under considera-
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tion. By contrast, the upper limit is set by the highest
dose tolerated without adverse pharmacologic effect. The
therapeutic window will differ between intranasal (topical) and oral (systemic) drug administration. The issues
discussed in this paper will focus on those pertaining to
oral H1-antihistamine administration.
Within any given therapeutic window for H1 antihistamines, a range of factors may influence the positioning
of any dose, such as coadministration of food, concomitant drug therapy (eg, macrolide antibiotics), concurrent
illness (eg, hepatic/renal disease), and pharmacologic
interactions (eg, alcohol). For example, fexofenadine,
which is licensed for the treatment of allergic rhinitis and
urticaria, is an H1 antihistamine with a very broad therapeutic window. It is clinically effective in a total daily dose
as low as 40 mg,1,2 which is one third of the clinically recommended dose. Moreover, it is free from adverse CNS
effects when assessed objectively at 3 times the standard
therapeutic dose (360 mg daily),3 and it is free from subjective reporting of sedation at 690 mg twice daily, a dose
almost 12 times the recommended daily dose.1 By contrast, the H1 antihistamine loratadine has a very narrow
therapeutic window, with the clinically recommended
dose of 10 mg appearing to be both the minimally effective dose and the maximum tolerated dose.4,5 Whereas
interactions or dose adjustments are highly unlikely to
influence the efficacy or safety of fexofenadine, they are
likely to have an effect with respect to loratadine.
H1-ANTIHISTAMINE ACTIVITY
The standard H1-antihistamine doses selected for
clinical evaluation are assessed both in the acute challenge situation to provide information on time to onset
of action, maximum inhibitory effect, and duration of
action and in naturally occurring clinical disease, which
has greater intrinsic variability and is less rigorously controlled than the challenge studies. These challenge and
“wild-disease” studies identify the H1-receptor antagonistic activity of all currently available H1 antihistamines
compared with placebo.6 This antagonistic activity, however, is least evident with loratadine,7 as one might anticipate when understanding the positioning of the
clinically recommended dose within the therapeutic
window. The receptor antagonistic activity of different
H1-receptor antagonists can be assessed by their suppression of histamine-induced wheal and flare, a commonly
used biologic assay for demonstrating the onset and
duration of peripheral H1-receptor blockade.8,9 This
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pharmacodynamic evaluation model is easily reproduced, allows objective assessments to be made in both
healthy volunteers and patients, and is useful as an addition to clinical studies.
WHEAL AND FLARE
Wheal and flare studies have been widely used to indicate in vivo differences in the potential efficacy of secondgeneration antihistamines.8-11 Frossard et al recently
compared the inhibition of histamine-induced wheal and
flare by fexofenadine HCl 180 mg, loratadine 10 mg, and
desloratadine 5 mg in a single-dose, randomized, parallelgroup, double-blind, placebo-controlled study of healthy
individuals.11 This study found that total inhibition of
wheal, as defined by the time required to achieve 95%
inhibition of wheal area, occurred between 3 and 3.5
hours following administration of fexofenadine. In contrast, total inhibition of wheal was not observed following
treatment with either loratadine or desloratadine at the
standard doses. These results are further corroborated in
the study by Kaliner et al.12 In this randomized, doubleblind, single-dose, placebo-controlled, cross- over study, it
was observed that fexofenadine HCl 180 mg was significantly more effective than loratadine 10 mg (P < .001) or
placebo (P < .05) at suppressing the flare response.
Fexofenadine wheal suppression was also significant relative to that of loratadine (P < .05) or placebo (P < .05).
In a similar study, Purohit et al compared the inhibition
of histamine-induced wheal and flare by single therapeutic doses of fexofenadine HCl 180 mg and cetirizine 10
mg in a single-center, double-blind, randomized, 2-way
crossover study.13 The findings showed that fexofenadine
Figure 1.Therapeutic Window
*The dose range over which a treatment is both effective and free from
unwanted side effects.
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and cetirizine are comparable in their time to occurrence
of 95% inhibition of the wheal and flare reaction to
histamine.
CLINICAL STUDIES
Although the histamine-induced wheal and flare
reaction is a useful clinical pharmacologic test to assess
dose-response relations for an antihistamine, thereby
providing an indication of its efficacy, data from clinical
studies are necessary to properly evaluate new agents. All
H1 antihistamines have been shown in placebo-controlled studies to be clinically efficacious.6 Studies comparing different H1 antihistamines allow evaluation of
both clinical efficacy and safety, and permit investigation
of the comparability of their profiles. The efficacy and
safety of once-daily fexofenadine 120 mg and 180 mg
and cetirizine 10 mg in the treatment of seasonal allergic
rhinitis (SAR) were compared in a multicenter, doubleblind, randomized, parallel-group, placebo-controlled,
14-day trial.14 A total symptom score (TSS) was generated as the sum of scores for the following symptoms:
sneezing, rhinorrhea, itchy nose/palate/throat, and
itchy/watery/red eyes. The findings revealed no significant differences in treatment efficacy between fexofenadine at either dose or cetirizine; however, cetirizine was
found to substantially induce fatigue and drowsiness, in
contrast to the results obtained with fexofenadine.
In a similar study, fexofenadine 180 mg and cetirizine
10 mg demonstrated statistically and clinically equivalent efficacy throughout the dosing period, based on TSS
in patients with moderate-to-severe SAR. This study also
assessed drowsiness using a visual analog scale (VAS) by
which scores were calculated based on a range from 0
(wide awake) to 100 (extremely sleepy). Differences in
VAS change from baseline between treatments were
observed; patients receiving fexofenadine consistently
reported less drowsiness than those receiving cetirizine.15
In a multicenter, multinational, double-blind, parallel-group, randomized, placebo-controlled 2-week study,
van Cauwenberge et al assessed the efficacy, safety, and
impact on quality of life (QOL) of once-daily fexofenadine HCl 120 mg, loratadine 10 mg, or placebo in the
treatment of SAR.16 Fexofenadine and loratadine were
significantly superior to placebo in reducing instantaneous TSS (P ≤ .0001 and P ≤ .005, respectively) and
individual 24-hour reflective symptom scores for sneezing, rhinorrhea, itchy nose/palate/throat, and itchy/
watery/red eyes (P ≤ .005 and P < .05, respectively;
Figure 2). In addition, fexofenadine was significantly
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superior to loratadine at improving nasal congestion and
itchy/watery/red eyes (P ≤ .05). All treatment groups had
significantly improved overall QOL from baseline
(P < .0001); however, the improvement in the fexofenadine group was significantly greater compared with the
loratadine (P ≤ .03) and placebo groups (P ≤ .005).
This difference between fexofenadine and loratadine
may be explained by their antagonist profile. Receptor
antagonists may be neutral antagonists or inverse agonists. Neutral antagonists inhibit the action of the relevant agonist but have no other intrinsic activity. Inverse
agonists, while inhibiting the action of the agonist, also
have additional activity independent of this property
through receptor binding. This binding alters the agonist-independent G-protein coupling of the receptor,
which contributes to the basal level of cell activation.
Inverse agonists will thus have a broader profile of effect
than pure neutral antagonists.17 Studies that we have
undertaken with fexofenadine in vitro indicate that it
acts as an inverse agonist in that it not only inhibits
tumor necrosis factor alpha–induced interleukin (IL)-8
release from epithelial cells, but also reduces the level of
IL-8 in the supernatant to below the unstimulated value.
The additional activity of fexofenadine over loratadine
on QOL and in relieving nasal obstruction in the study
by van Cauwenberge et al could be explained by its ability to act as an inverse agonist.16
DRUG-DRUG INTERACTIONS
The coadministration of other drugs or pharmacologically active agents may potentially modify the positioning of an H1 antihistamine within the therapeutic
window by, for example, interfering with absorption or
metabolism. Such changes may either reduce clinical
efficacy or increase the risk of side effects. These possible
consequences became most apparent when drug interactions led to the appreciation that astemizole and terfenadine had potentially serious cardiac effects due to their
inhibitory actions on the potassium rectifier currents
within the myocardium.18 Both astemizole and terfenadine undergo hepatic metabolism involving the
cytochrome P450 isoenzymes. The coadministration of
macrolide antibiotics, such as erythromycin, or antifungal agents, such as ketoconazole, which share the same
P450 isozymes, led to the inhibition of their metabolism
and a rise in their plasma levels. This interaction took
these drugs out of their therapeutic window, with the
potentially fatal, although very rare, consequence of the
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Figure 2. Placebo-Controlled Comparison of
Fexofenadine and Loratadine in Seasonal Allergic
Rhinitis
Adapted with permission from van Cauwenberge et al. Comparison of the
efficacy, safety, and quality of life provided by fexofenadine hydrochloride
120 mg, loratadine 10 mg, and placebo administered once daily for the
treatment of seasonal allergic rhinitis. Clin Exp Allergy. 2000;30(6):891899.16 Blackwell Publishing.
ventricular arrhythmia, torsade de pointes. H1 antihistamines that do not undergo hepatic metabolism, such as
fexofenadine and cetirizine, are thus free from these
cytochrome P450 interactions.
Interest has more recently focused on the relevance
of pharmacologic interactions involving the superfamily of adenosine triphosphate-binding cassette proteins, such as P-glycoprotein (Pgp) and other carrier
protein families, including the organic anion transporting peptide (OATP) family.19 Pgp is an important
transport protein regulating clearance of molecules
that penetrate the blood-brain barrier. Substrates for
this carrier protein are rapidly cleared from the CNS
and thus are not available to act on central receptors.
Fexofenadine is an excellent Pgp substrate; this property makes it a safe H1 antihistamine regarding CNS
sedative effects (see review by Prof Hindmarch for
details of CNS effects of H1 antihistamines).20
Pgp is also involved in eliminating drugs across the
gastrointestinal mucosa. At this site, ketoconazole and
macrolide antibiotics are known to inhibit Pgp, reducing
the gastrointestinal elimination of H1 antihistamines
that use this transport mechanism. For example, ketoconazole increases the plasma levels of desloratadine, and
azithromycin increases the plasma levels of both desloratadine and fexofenadine.21,22 By contrast, the OATP
family helps facilitate the gastrointestinal absorption of
certain H1 antihistamines. This transport process is susceptible to inhibition by grapefruit juice.23,24 Studies in a
small number of healthy volunteers have reported a
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decrease in the plasma levels of fexofenadine when taken
with large quantities (1.2 L) of double-strength grapefruit juice.24 This reduction is, however, only about 30%
and, due to the minimally effective dose being substantially lower than the effects of this reduction, there is no
clinical consequence. Individuals would be unlikely to
consume quantities of grapefruit juice large enough to
effect this level of reduction. Consistent with the lack of
clinical significance of this interaction, data from White
et al demonstrated that fexofenadine significantly
inhibits the histamine wheal and flare response within
the skin when oral fexofenadine is coadministered with
either grapefruit juice or orange juice.25,26
Changes in the positioning of H1 antihistamines
within a narrow therapeutic window will, however, lead
to clinical consequences. The significance of the 40%
increase in plasma levels of desloratadine when coadministered with ketoconazole is undetermined, as much
less is known about the therapeutic window of this antihistamine. It is appreciated, however, that increasing the
dose of drugs that have a therapeutic dose at the top end
of their therapeutic window, such as cetirizine and
loratadine, can lead to central effects, such as sedation
and cognitive impairment.5 These effects could become
an issue in situations in which patients overmedicate
beyond the prescribed dose due to inadequate symptom
control of either rhinitis or urticaria.
GENETIC INFLUENCES
Variations in the population and among different
racial populations, in terms of the metabolism of antihistamines, may theoretically alter the position of a certain drug within its known therapeutic window. Little is
known about how this variable influences either the efficacy or the side-effect profile of the currently available
H1-receptor antagonists. Any impact of metabolic alterations will, as for the other considerations, be more relevant to those drugs with a narrow therapeutic window,
those that are administered either at the lower or upper
end of this range, and those for which small alterations
can take them outside their therapeutic window. The
product insert for desloratadine indicates that certain
populations of patients are thought to be slow metabolizers of this agent. Approximately 7% of the general
population and 20% of the black population have difficulty in converting desloratadine to its active metabolite,
3-hydroxydesloratadine, and may be more susceptible to
dose-related adverse events.27 Additional investigation of
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this issue is warranted to understand differences in individual susceptibility within the population and to better
inform physicians regarding choice of antihistamine.
CONCLUSION
The appreciation of the therapeutic window for any
antihistamine and the positioning of the medication
within this window allow an easy evaluation of the likely impact of any dose changes or interactions that will
either decrease or increase the bioavailability of that
medication. Ideally, an antihistamine should be positioned centrally within a broad therapeutic window.
Under such circumstances, those influences that alter
bioavailability are unlikely to have any clinical consequence, and the drug can be prescribed without concern.
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