Systemic bioavailability (BA) and pharmacodynamics (PD) of fluticasone propionate/formoterol (FP/FORM) via pressurised metered-dose inhaler (pMDI) or a novel breath-triggered inhaler (BTI)

Background: Two-stage (S1, S2) adaptive design study to compare systemic BA and PD of FP and FORM via the BTI (Flutiform® K-haler®), and pMDI with (+S) or without a spacer (EudraCT: 2013-000045-39). Methods: Single-dose, randomised, open-label crossover study in healthy adults. S1 assessed pharmacokinetics (PK): 3 period, 3 treatment (FP/FORM 125/5µg 2puffs via BTI, pMDI or pMDI+S). Primary endpoints: AUCt and Cmax. Primary comparisons: for FP, BTI vs pMDI+S; for FORM, BTI vs pMDI (safety confirmed if upper limits of 94.12% confidence intervals [CI] of ratios ≤125%). S2, conducted if S1 primary comparison CI >125%, assessed FORM PD (given S1 outcome): 5 period, 5 treatment (FP/FORM 125/5µg 12puffs via BTI, pMDI or pMDI+S; FP/FORM 125/5µg 4puffs via pMDI; FORM 12µg 5puffs via pMDI). Primary endpoint: maximum reduction in serum potassium within 4h post‑dose. Equivalence: 95% CI for BTI vs pMDI+S and pMDI ratios within 0.5-2. Blood samples were taken up to 36h (S1) or 6h (S2). Results: S1: 43/48 subjects completed. Upper limit (UL) of CIs for FP via BTI vs pMDI+S: AUCt 91.4%, Cmax 87.1%; for FORM via BTI vs pMDI: AUCt 124.1%, Cmax 126.0%. S2: 30/35 subjects completed. The 95% CIs for serum potassium were: BTI vs pMDI+S 0.73-1.28; BTI vs pMDI 0.43-1.46. Conclusion: Systemic exposure of FP via BTI was no greater than pMDI+S; FORM Cmax marginally exceeded 125% UL (S1). S2 confirmed FORM-related systemic safety was similar via BTI, pMDI+S and pMDI. These data support the safety of the Flutiform K-haler product. Sponsor: Mundipharma Research Ltd