A methacholine challenge dose-response study for development of a pharmacodynamic bioequivalence methodology for albuterol metered- dose inhalers.
BACKGROUND
With the expiration of the patent on albuterol metered-dose inhalers (MDIs) in 1989, methods to assess in vivo bioequivalence of generic formulations required investigation.


OBJECTIVE
In an effort to develop a sensitive method to document bioequivalence, bronchoprovocation with methacholine chloride was used to assess the dose-response relationship of albuterol as delivered by MDI. Sensitivity was assessed in terms of magnitudes of ED(50), the estimated albuterol dose required to achieve 50 % of the fitted maximal value of the pharmacodynamic effect above baseline, and change in response as a function of dose, with emphasis on 1 and 2 actuations.


METHODS
On separate study days, 15 nonsmokers with mild asthma received randomized nominal albuterol doses of 0 to 576 microg by using specially manufactured MDI canisters. FEV(1) was measured 15 minutes after MDI dosing. Serially increasing doses of methacholine were administered, and FEV(1) was measured after each methacholine dose until a 20 % decrease in FEV(1) (PD(20)) was achieved.


RESULTS
Mean PD(20) values after use of each of the albuterol-containing MDIs were significantly greater than either mean screening or mean placebo PD(20) values (P <.05). Mean responses and most individual subject responses to 1 and 2 actuations (90 and 180 microg) of albuterol MDI were within the sensitive region of the dose- response curve. The mean estimated ED(50) value on the basis of nonlinear mixed effect modeling was 119.2 microg (range, 33.3-337.1 microg), with an intersubject percentage coefficient of variation of 69.0 %.


CONCLUSIONS
The methacholine bronchoprovocation model is safe and useful in the study of albuterol MDI dose-response in asthmatic subjects. Bronchoprovocation studies may be used for determination of bioequivalence of multisource albuterol MDI products.
Creticos
Peter S
PS
Department of Medicine, Division of Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Adams
Wallace P
WP
Petty
Brent G
BG
Lewis
Lionel D
LD
Singh
Gur Jai Pal
GJ
Khattignavong
Arouna P
AP
Molzon
Justina A
JA
Martinez
Marilyn N
MN
Lietman
Paul S
PS
Williams
Roger L
RL
D000280:Administration, Inhalation; D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage / Q000494:pharmacology*; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy; D001499:Bayes Theorem; D001985:Bronchial Provocation Tests / Q000379:methods*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D016210:Methacholine Chloride / Q000494:pharmacology*; D012680:Sensitivity and Specificity
D000318:Adrenergic beta-Agonists; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D016210:Methacholine Chloride; D000420:Albuterol