Am. J. Respir. Crit. Care Med., Volume 160, Number 1, July 1999, 354-357

Protection against Methacholine Bronchoconstriction to Assess Relative Potency of Inhaled ₂-Agonist

KRISHNAN N. PARAMESWARAN, MARK D. INMAN, BRUCE P. EKHOLM, MARILYN M. MORRIS, EDIE SUMMERS, PAUL M. O'BYRNE, and FREDERICK E. HARGREAVE

Asthma Research Group, Departments of Medicine, St. Joseph's Hospital and McMaster University, Hamilton, Ontario, Canada; and Statistical Data Services, 3M Pharmaceuticals Ltd., 3M Center, St. Paul, Minnesota

The purposes of this study were to estimate the relative dose potency (RP) of two formulations of salbutamol pressurized metered-dose inhalers (Proventil-HFA and Ventolin-CFC MDIs) to protect against methacholine bronchoconstriction, to validate this method and provide recommendations. The protective effects of 100-, 200-, and 400-µg doses of Proventil-HFA were compared with the same doses of Ventolin-CFC in 18 adult asthmatics (mean FEV₁, 92% predicted; mean baseline PC₂₀ methacholine, 1.8 mg/ml), in a dose-level blind, balanced, eight-period, crossover, placebo-controlled study. The log-transformed PC₂₀ values after each dose of the drugs were compared by repeated-measures analysis of variance (ANOVA). A significant dose-effect was present (p < 0.0001). Using the Finney assay, the RP of Proventil-HFA compared with Ventolin-CFC was 1.08 (90% CI, 0.81-1.46) (80% power). This was also estimated using a nonlinear E_max model to validate the Finney method. The most precise estimate of RP was obtained with the comparison between 100- and 200-µg doses (RP, 1.00; 90% CI, 0.77-1.31). There were no adverse events resulting from the drugs or methacholine. We conclude that Proventil-HFA salbutamol is bioequivalent to Ventolin-CFC salbutamol. Bronchoprotection to methacholine is a valid method of demonstrating bioequivalence. By this method, 100- and 200-µg doses of salbutamol inhalations from an MDI will suffice.

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