Bioassay of Salmeterol in Children Using Methacholine Challenge With Impulse Oscillometry

Background: Bronchoprovocation with methacholine (MC) is the most sensitive method of determining bioequivalence of inhaled bronchodilators. FEV1 is used to determine the endpoint, but many children cannot perform spirometry reproducibly. The purpose of this study was to determine whether MC, using impulse oscillometry (IOS) as the endpoint, can differentiate between two doses of salmeterol (SM). Methods: This was a single-blind, randomized study of 10 subjects with mild stable asthma, ages 4-11 years. None were taking a long-acting beta-agonist but most were on low-dose inhaled corticosteroid. On one study day, MC was performed 1 hr after one inhalation from each of two separate Advair 100/50 Diskus (100 mu g salmeterol treatment). On a second day, MC was performed after one inhalation from Advair Diskus and one inhalation from Flovent Diskus 100 (50 mu g salmeterol treatment). The provocative concentration of methacholine causing a 40% increase in total airway resistance (PC40R5) was calculated. Results: The reduction in R-5 (bronchodilator effect) was 15.5% and 18.4% for 50 and 100 mu g, respectively (NS). After MC (bronchoprotective effect), the geometric mean (95% CI) PC40R5 (mg/ml) was 2.4 (1.3-4.4) during screening, 22.9 (8.5-61.6) after 50 mu g SMand 47.0 (25.2-87.8) after 100 mu g SM (P = 0.051 for 50 vs. 100 using a linear mixed effects model). No adverse effects were observed. Conclusions: MC with IOS endpoint will be a useful method for determining bioequivalence of a generic inhaler in children. Seventy-two subjects will be required to achieve 80% power to assess bioequivalence of SM. (C) 2015 Wiley Periodicals, Inc.