Sensitivity of disease parameters to flexible budesonide/formoterol treatment in an allergic rat model.
BACKGROUND
Clinical studies show that flexible dosing (maintenance and symptom-driven dose adjustments) of budesonide and formoterol (BUD/FORM) improves control of asthma exacerbations as compared to fixed maintenance dosing protocols (maintenance therapy) even when the latter utilize higher BUD/FORM doses. This suggests that dose-response relationships for certain pathobiologic mechanisms in asthma shift over time. Here, we have conducted animal studies to address this issue.


OBJECTIVE
(1) To test in an animal asthma-like model whether it is possible to achieve the same or greater pharmacological control over bronchoconstriction and airway/lung inflammation, and with less total drug used, by flexible BUD/FORM dosing (upward adjustment of doses) in association with allergen challenges. (2) To determine whether the benefit requires adjustment of both drug components.


METHODS
Rats sensitized on days 0 and 7 were challenged intratracheally with ovalbumin on days 14 and 21. On days 13-21, rats were treated intratracheally with fixed maintenance or flexible BUD/FORM combinations. On day 22, rats were challenged with methacholine and lungs were harvested for analysis.


RESULTS
A flexible BUD/FORM dosing regimen (using 3.3 times less total drug than the fixed maintenance high dose regimen), delivered the same or greater reductions of excised lung gas volume (a measure of gas trapped in lung by bronchoconstriction) and lung weight (a measure of inflammatory oedema). When either BUD or FORM alone was increased on days of challenge, the benefit of the flexible dose upward adjustment was lost.


CONCLUSIONS
Flexible dosing of the BUD/FORM combination improves the pharmacological inhibition of allergen-induced bronchoconstriction and an inflammatory oedema in an allergic asthma-like rat model.
Brange
Charlotte
C
AstraZeneca R&D Lund, Scheelevagen 8, SE 221 87 Lund, Sweden. charlotte.brange@astrazeneca.com
Smailagic
Amir
A
Jansson
Anne-Helene
AH
Middleton
Brian
B
Miller-Larsson
Anna
A
Taylor
John D
JD
Silberstein
David S
DS
Lal
Harbans
H
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000494:pharmacology; D019819:Budesonide / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage* / Q000494:pharmacology; D000068759:Formoterol Fumarate; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010047:Ovalbumin; D051381:Rats; D011914:Rats, Inbred BN; D013997:Time Factors
D001993:Bronchodilator Agents; D004338:Drug Combinations; D004983:Ethanolamines; D019819:Budesonide; D010047:Ovalbumin; D000068759:Formoterol Fumarate