Group Title: Respiratory Research
Title: Relative receptor affinity comparisons among inhaled/intranasal corticosteroids: perspectives on clinical relevance
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 Material Information
Title: Relative receptor affinity comparisons among inhaled/intranasal corticosteroids: perspectives on clinical relevance
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Language: English
Creator: Hochhaus,Günther
Publisher: Respiratory Research
Publication Date: 2008
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Abstract: BACKGROUND:Pharmacokinetic properties, dosing regimen, and potency at the site of action are among the factors that influence activity of a corticosteroid. The potency of a corticosteroid at the site of action is determined significantly by its affinity to the glucocorticoid receptor. Recent literature on topical corticosteroids reveals an increasing emphasis on comparative relative receptor affinity values as a key method of differentiating among various corticosteroid compounds, particularly with regard to clinical efficacy.METHODS:A response was formulated to: Valotis A, Högger P: Human receptor kinetics and lung tissue retention of the enhanced-affinity glucocorticoid fluticasone furoate. Respir Res 2007, 8:54.RESULTS:Relative receptor binding affinities, while often showing significant variability across different laboratories, are a valid parameter when a comparison of the pharmacological activity of various glucocorticoids at the site of action is desired. Unfortunately within this context, scientific literature including the article from Valotis and Högger, confuse differences in potency (concentration or dose necessary to achieve a certain effect) with differences in efficacy (a quantitative difference in the overall maximum effect, even if all the receptors are occupied). All glucocorticoids will show the same efficacy as long as the selected dose will occupy the same number of receptors.CONCLUSION:While relative receptor affinities are useful for comparing in vitro potencies of corticosteroids, these data are not representative of physiologic conditions and should not be used as a basis for comparing the presumed effectiveness of compounds in a clinical situation.
General Note: Start page 75
General Note: M3: 10.1186/1465-9921-9-75
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Volume ID: VID00001
Source Institution: University of Florida
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Rights Management: Open Access: http://www.biomedcentral.com/info/about/openaccess/
Resource Identifier: issn - 1465-9921
http://respiratory-research.com/content/9/1/75

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Letter to the Editor

Relative receptor affinity comparisons among inhaled/intranasal
corticosteroids: perspectives on clinical relevance
Ginther Hochhaus


Address: University of Florida College of Pharmacy, Gainesville, Florida, USA
Email: Giinther Hochhaus hochhaus@cop.ufl.edu


Published: 24 November 2008
Respiratory Research 2008, 9:75 doi: 10.1 186/1465-9921-9-75


Received: 16 May 2008
Accepted: 24 November 2008


This article is available from: http://respiratory-research.com/content/9/l/75
2008 Hochhaus; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.ore/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



Abstract
Background: Pharmacokinetic properties, dosing regimen, and potency at the site of action are
among the factors that influence activity of a corticosteroid. The potency of a corticosteroid at the
site of action is determined significantly by its affinity to the glucocorticoid receptor. Recent
literature on topical corticosteroids reveals an increasing emphasis on comparative relative
receptor affinity values as a key method of differentiating among various corticosteroid
compounds, particularly with regard to clinical efficacy.
Methods: A response was formulated to: Valotis A, Hogger P: Human receptor kinetics and lung
tissue retention of the enhanced-affinity glucocorticoid fluticasone furoate. Respir Res 2007, 8:54.
Results: Relative receptor binding affinities, while often showing significant variability across
different laboratories, are a valid parameter when a comparison of the pharmacological activity of
various glucocorticoids at the site of action is desired. Unfortunately within this context, scientific
literature including the article from Valotis and Hogger, confuse differences in potency
(concentration or dose necessary to achieve a certain effect) with differences in efficacy (a
quantitative difference in the overall maximum effect, even if all the receptors are occupied). All
glucocorticoids will show the same efficacy as long as the selected dose will occupy the same
number of receptors.
Conclusion: While relative receptor affinities are useful for comparing in vitro potencies of
corticosteroids, these data are not representative of physiologic conditions and should not be used
as a basis for comparing the presumed effectiveness of compounds in a clinical situation.


Topical corticosteroids, such as beclomethasone dipropi-
onate, budesonide, triamcinolone acetonide, flunisolide,
ciclesonide, mometasone furoate (MF), fluticasone propi-
onate (FP), and fluticasone furoate (FF) are first-line treat-
ments for upper respiratory allergic conditions such as
asthma and seasonal/perennial rhinitis, as they provide
local efficacy and, thereby, reduce systemic glucocorticoid
exposure [1-4]. In recent literature, comparative relative


receptor affinity (RRA) values for glucocorticoid receptors
in nasal/lung tissue are increasingly used to differentiate
among topical corticosteroids. In many instances, the
presentation of RRA data and rank ordering of com-
pounds is accompanied by overt or subtle implications of
clinical efficacy ramifications. While RRA has a rightful
place in the comparison of in vitro potency of corticoster-
oids, practicing clinicians need to understand the limita-


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http://respiratory-research.com/content/9/1/75


tions of such data when they are used as arguments for the
clinical efficacy of a given glucocorticoid.

As a case in point, I refer to a recent publication in Respi-
ratory Research (2007:8:54) in which Valotis and H6gger
report data comparing the glucocorticoid-receptor and
lung-tissue binding affinities of FF, FP, and MF [5] While
the methodology of the study and the resulting data are
sound, the authors imply, that a high receptor affinity,
such as the one reported in this publication for FF,
improves the local efficacy of a topical glucocorticoid (see
Background section of the article) and that the high rela-
tive receptor affinity of the "enhanced-affinity" FF "that
exceeds the RRAs of all other clinically used glucocorti-
coids" "may contribute to a highly efficacious profile for
FF". To be fair, H6gger's group is not the only one confus-
ing potency and efficacy of inhaled glucocorticoids, as the
interchangeable use of the two terms can be found
throughout the literature, often with the underlying
assumption that a high affinity glucocorticoid must be the
better one. The clinical and pharmacologic reality, how-
ever, is that "potency" and "efficacy" are not interchange-
able terms and that differences in the receptor affinity do
not necessarily translate into differences in local or clini-
cal efficacy. It only indicates that for a "weaker" glucocor-
ticoid, higher concentrations at the site of action are
necessary to achieve the same pharmacodynamic effect. In
the clinical setting, differences in potency, therefore can
be overcome by adjusting the dose [6]. Therefore, two glu-
cocorticoids that differ only in the receptor binding affin-
ity (e.g. by 25%) would show the same clinical efficacy
and systemic side effects when the "weaker" steroid is
given at a 25% higher dose.

In summary, while it is not my intent to discredit the
importance of studying RRA, I am recommending caution
in the interpretation of and reliance on such data, partic-
ularly when claims of clinical distinction are drawn. As
recent pharmacokinetic/pharmacodynamic evaluations
have shown, the topical selectivity and local targeting of
glucocorticoids is independent of the binding affinity and
solely determined by pharmacokinetic properties [7].

Abbreviations
FF: fluticasone furoate; FP: fluticasone propionate; MF:
mometasone furoate; RRA: relative receptor affinity.

Competing interests
During the preparation of this letter to the editor, the
author has been provided talks for Schering-Plough, con-
sulted for Verus Pharmaceuticals and WAX and received
grants from AstraZeneca.

Authors' contributions
GH is the author of this commentary.


Acknowledgements
Editorial assistance was provided by Sandra Westra, Pharm D, and Chris-
tina Sullivan-Sarabhai. This assistance was funded by Schering-Plough.

References
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British guideline on the management of asthma: a national
clinical guideline. Revised edition. 2007 [http://www.brit-tho
racic.org.uk/c2/uploads/asthma fullguideline2007.pdf].
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Guidelines for the diagnosis and management of asthma.
FullReport. 2007 [http://www.nhlbi.nih.gov/guidelines/asthma/asth
gdln.pdf].
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5. Valotis A, Hogger P: Human receptor kinetics and lung tissue
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6. Hochhaus G: Pharmacokinetic/pharmacodynamic profile of
mometasone furoate nasal spray: potential effects on clinical
safety and efficacy. Clin Ther 2008, 30(I): I-13.
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