Systemic exposure and lung bioavailability across two different dose strengths of CHF5993 a novel Triple pMDI

Abstract

Introduction: CHF 5993 pMDI is a new fixed triple combination of extrafine Beclomethasone Dipropionate (BDP), Formoterol Fumarate (FF) and Glycopyrronium Bromide (GB) being developed in asthma as medium strength, 100/6/12.5µg/actuation (MS), and a high strength, 200/6/12.5 µg/actuation(HS) formulation. Objective: To assess the proportionality of BDP/B17MP (active metabolite of BDP) and the equivalence of FF and GB in terms of systemic and lung exposure, between the two strengths. Methods: Open label, randomized, single-dose, five-way crossover study in 47 healthy volunteers. Subjects received four inhalations of each strength with charcoal block (to assess the lung exposure) and without charcoal block (to assess the systemic exposure) and placebo. Pharmacokinetics of BDP/B17MP, FF and GB, as well as cardiovascular and systemic effects were studied Results: BDP and B17MP systemic and lung exposure were dose-proportional between HS and MS. GB and FF systemic and lung exposure were equivalent between the two strengths. After administration of HS, GB C max increased by 22% and 13% with and without charcoal block, respectively, compared to MS. However, this increase did not result in any clinically relevant change in cardiac and systemic effects or a higher incidence of AEs. No clinically relevant effects on heart rate, ECG parameters, vital signs, potassium, and glucose levels was observed after administration of either strength compared to placebo with no difference between HS and MS. Conclusions: Total systemic exposure and lung bioavailability of BDP/B17MP were proportional between the two strengths. FF and GB exposure was equivalent for the two strengths.