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 ED50, 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 mug by using specially manufactured MDI canisters. FEV1 was measured 15 minutes after MDI dosing. Serially increasing doses of methacholine were administered, and FEV1 was measured after each methacholine dose until a 20% decrease in FEV1 (PD20) was achieved. Results: Mean PD20 values after use of each of the albuterol-containing MDIs were significantly greater than either mean screening or mean placebo PD20 values (P < .05). Mean responses and most individual subject responses to 1 and 2 actuations (90 and 180 mug) of albuterol MDI were within the sensitive region of the dose-response curve. The mean estimated ED50 value on the basis of nonlinear mixed effect modeling was 119.2 mug (range, 33.3-337.1 mug), 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.