A Dose–Response Study to Examine the Methodology for Demonstrating the Local Therapeutic Equivalence of the Fluticasone Propionate Component of an Orally Inhaled Combination Therapy of Fluticasone Propionate/Salmeterol Dry Powder

Abstract

Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta-agonist combinations, such as fluticasone propionate/salmeterol (FPS) dry powder inhaler. Some regulators require generic medications to demonstrate local therapeutic equivalence (LTE) for each component of the FPS reference product. Fractional exhaled nitric oxide (FeNO) was developed as a possible LTE endpoint for the fluticasone propionate (FP) component of FPS in a randomized, double-blind, crossover study in steroid-naive asthma patients with elevated FeNO (≥45 parts per billion). Methods: Thirty-four patients received three of five treatments: FPS 100/50 μg once daily (QD), FPS 100/50 μg twice daily (BID), FPS 250/50 μg BID, FPS 500/50 μg BID, or placebo, each for 2 weeks separated by 14-day washout. FeNO was measured on days 1, 2, 3, 5, 7, and 14 of each period, according to American Thoracic Society standards. Results: FPS treatments decreased FeNO compared with placebo, with the largest differentiation between doses noted on day 14; the mean decreases from days 1 to 14 ranged from -46.6% to -64.5% with FPS versus -9.1% with placebo. The dose-response plateaued at 200 μg/day (FPS 100/50 μg BID). Linear regression analysis revealed significant slopes between FPS doses, with the steepest between 100/50 μg QD and 100/50 μg BID (-0.0039, p = 0.020). An estimated sample size (SS) of 160 or 48 patients would be required to demonstrate LTE of generic and FPS reference products (0.80-1.25 and 0.67-1.50 bioequivalence limits, respectively). However, as the slope between BID FPS doses was shallow, a larger SS may be needed if only an approved dose regimen was used. Conclusion: FeNO could be a valid endpoint to determine LTE between the FP component of generic and reference FPS products, but only if QD dosing and wide equivalence limits are included. As QD dosing is not an approved regimen, this approach is unlikely to be acceptable.