Pharmacokinetics Of Mometasone Furoate Delivered Via Two Dry Powder Inhalers

Background: QMF149 is an inhaled fixed-dose combination of indacaterol acetate and mometasone furoate (MF) delivered via Breezhaler (R), under development for once-daily treatment of asthma. MF delivered via Twisthaler (R) is approved as Asmanex (R) Twisthaler (R) for the treatment of asthma. Bridging of MF delivered via Twisthaler (R) to MF delivered via Breezhaler (R) was undertaken as part of QMF149 development to enable dose comparisons between the devices. Pharmacokinetics (PK) of MF were characterized in two studies; a single dose PK study in healthy volunteers and a pharmacokinetic/pharmacodynamic (PK/PD) study in asthma patients.Objectives: The PK study in healthy volunteers evaluated the PK of single doses of MF via Breezhaler (R) (50-400 mu g) and compared systemic exposure of MF following administration via Breezhaler (R) and Twisthaler (R) 400 mu g (2 inhalations of 200 mu g). The study in patients with asthma characterized the MF PK profile following once-daily inhalation of MF via Breezhaler (R) and Twisthaler (R) devices for 4 weeks.Methods: In the open-label, single-dose, crossover study, healthy subjects sequentially received MF via Twisthaler (R) (400 mu g, medium-dose inhaled corticosteroid [ICS]) and escalating doses via Breezhaler (R) (50, 100, 200, 400 mu g). PK data were obtained up to 72 h post-dose. In the double-blind, double-dummy, parallel-group study, asthma patients were randomised to receive either MF 80 mu g (low-dose ICS) or 320 mu g (high-dose ICS) via Breezhaler (R), or 200 mu g (low-dose ICS) or 800 mu g (2 inhalations of 400 mu g; high-dose ICS) via Twisthaler (R) once daily for 4 weeks. PK sampling was performed on Days 1 and 28 at pre-dose and up to 24 h post-dose.Results: In the healthy volunteer PK study, 20 healthy subjects completed all treatments. Dose-normalised AUC(l)(ast) of MF was 1.8-1.9-fold higher when delivered via Breezhaler (R) versus Twisthaler (R). AUC(last) and C-max of MF increased in a dose-proportional manner over the range of 50-400 mu g via Breezhaler (R). Results from this study guided dose selection of MF via Breezhaler (R) for the asthma study. In the asthma study, in a subset of 96 patients, mean systemic exposure (AUC(l)(ast) and C-max) for MF 80 and 320 mu g via Breezhaler (R) was comparable with MF 200 and 800 mu g via Twisthaler (R), respectively, on Day 28.Conclusion: PK characterization in a healthy volunteer PK study and subsequently an asthma study enabled selection of 80 mu g (low), 160 mu g (medium), and 320 mu g (high) delivered via Breezhaler (R) as MF doses comparable to the 200 ug, 400 mu g and 800 mu g doses delivered by Twisthaler (R), respectively, as part of QMF149 formulation development.