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Background and Objective: Clinical evidence suggests no clinically relevant pharmacokinetic interactions between indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF). A population pharmacokinetic (popPK) analysis was conducted to identify structural models describing systemic pharmacokinetic profiles of IND, GLY and MF, and estimate the effect of covariates on their pharmacokinetics following inhalation as IND/GLY/MF., Methods: Pharmacokinetic data from 698 patients with asthma were pooled from two Phase III studies that evaluated IND/MF medium- (150/160 µg) and high-dose (150/320 µg), IND/GLY/MF medium- (150/50/80 μg) and high-dose (150/50/160 μg), and a device bridging Phase II study with MF. One popPK model was developed each for IND, GLY and MF using a nonlinear mixed-effect modelling approach. Maximal and trough plasma concentrations were compared across formulations and studies, including data for IND/GLY from chronic obstructive pulmonary disease (COPD) patients. The effect of predefined covariates on the pharmacokinetics of components was evaluated using a full covariate modelling approach., Results: The final pharmacokinetic models were two-compartment disposition models with first-order elimination and sequential zero-order/first-order absorption (IND), with bolus administration and first-order elimination (GLY), and with mixed zero-order/first-order absorption and first-order elimination (MF). All model parameters were estimated with good precision (% relative standard error: IND and MF ≤25%; GLY <10%). No clinically relevant covariate effect was observed on the pharmacokinetics of IND, GLY and MF. IND and GLY pharmacokinetic profiles were similar across different formulations., Conclusion: Two-compartment popPK models adequately described the pharmacokinetics of IND, GLY and MF. The effect of covariates was not clinically relevant. The pharmacokinetic profiles of MF were comparable for combination products at corresponding medium- or high-dose inhaled corticosteroids. On a population level, the pharmacokinetics of IND and GLY were comparable between patients with asthma and COPD., (© 2021. The Author(s).)

Introduction: Mometasone furoate (MF) is the inhaled corticosteroid (ICS) component in the long-acting β 2 -agonist (LABA)/ICS fixed-dose combination of indacaterol/MF, delivered via Breezhaler®, in development for asthma. MF at low (80 μg) and high (320 μg) doses delivered via Breezhaler® is expected to be comparable to MF at low (200 μg) and high (800 μg) doses respectively, delivered via Twisthaler®., Methods: This was a randomized, double-blind, double-dummy, four-week, parallel-group study of 739 adolescents and adults with persistent asthma. Eligible patients were receiving ICS treatment up to the maximum dose per day on a stable regimen for at least four weeks before screening. The study population was enriched for patients who were responsive to ICS therapy. The primary objective of the present study was to show non-inferiority of these doses, i.e. the low (80 μg) and high (320 μg) doses of MF delivered via Breezhaler® once daily, compared with the corresponding low (200 μg) and high (800 μg) doses of MF delivered via Twisthaler® once daily. The primary endpoint was 24 h post-dose trough forced expiratory volume in 1 s (FEV 1 ), after four weeks of treatment in patients with asthma. A secondary objective was to evaluate the efficacy of MF 80 μg and 320 μg delivered via Breezhaler®, and MF 200 μg and 800 μg delivered via Twisthaler® in terms of Asthma Control Questionnaire-5 (ACQ-5) after one, two, three and four weeks of treatment., Results: The LS mean difference in trough FEV 1 after four weeks of treatment between MF low dose 80 μg (Breezhaler®) and MF low dose 200 μg (Twisthaler®) was 27 mL (95% CI -34, 89); for MF high dose 320 μg (Breezhaler®) and MF high dose 800 μg (Twisthaler®) the difference was 0 mL (95% CI -60, 61). These differences were neither clinically nor statistically significant. All treatment arms provided similar clinically relevant improvements in ACQ-5 after four weeks of treatment compared with baseline. Both treatments showed a similar safety profile with a low incidence of adverse events., Conclusion: The similarities in effects on lung function and ACQ after four weeks of treatment demonstrate the comparability of MF at low (80 μg) and high (320 μg) doses delivered with Breezhaler® with MF at low (200 μg) and high (800 μg) doses delivered with Twisthaler®, respectively. The study formally demonstrated that MF, delivered via Breezhaler®, is non-inferior to MF, delivered via Twisthaler® at corresponding ICS doses., Competing Interests: Declarations of competing interest RB reports grants to Mainz University and personal fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche, as well as personal fees from AstraZeneca, Chiesi, Cipla, Sanofi and Teva, all outside the submitted work. AMT, MH, ID, FP, BH and HCT are employees of Novartis Pharma AG and own Novartis Pharma AG shares. WC is an employee of Novartis Pharmaceuticals Corporation. CB and JJ are employees of Novartis Pharma AG. DZ is an employee of Novartis Pharma AG and owns Novartis Pharma AG shares. DZ has led the development of Breezhaler® dry powder inhaler and was the technical project leader for the development of the Breezhaler® mometasone drug product. FK reports personal grants or fees for scientific work, presentations and Advisory boards in the last 5 years from Mundipharma, Astra Zeneca, Novartis and TEVA. However, all of these are outside the submitted work., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)