Soniya S Vaidya1, Sanjeev Khindri2, Nicole Calder2, Surendra Machineni3, Hisanori Hara4, Tapan Majumdar5, Salvatore Febbraro6, Rainard Fuhr7, Ralph Woessner4. 1. Drug Metabolism and Pharmacokinetics, Clinical Pharmacokinetics/Pharmacodynamics, Novartis Institutes for BioMedical Research, Cambridge, MA, USA. Electronic address: soniya.vaidya@novartis.com. 2. Translational Medicine, Novartis Institutes for BioMedical Research, Horsham, UK. 3. Integrated Information Sciences, Novartis Healthcare Pvt. Ltd., Hyderabad, India. 4. Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland. 5. Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA. 6. Simbec Research Ltd., Merthyr Tydfil, UK. 7. Early Phase Clinical Unit, PAREXEL, Berlin, Germany.
Abstract
PURPOSE: QMF149 is a fixed-dose combination of the long-acting β2 agonist, indacaterol and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic (PK) and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler(®) device, either alone or in a free or fixed combination (QMF149) in healthy adult subjects. METHODS: In this randomized, open-label, four-way crossover study, subjects were randomized to receive indacaterol acetate 150 μg, mometasone furoate 320 μg, alone and as free combination of the individual components, or QMF149 (indacaterol acetate 150 μg/mometasone furoate 320 μg) once daily for 14 days in each period, followed by a 7-day washout between periods. PK profiles were characterized on Day 14 up to 168 h post-dose. RESULTS: Indacaterol AUC0-24h,ss and Cmax,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC0-24h,ss and Cmax,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], higher, respectively than mometasone furoate monotherapy. The majority (three of four comparisons between QMF149 and monotherapy) of the 90% confidence intervals of the between-treatment ratios for AUC0-24h,ss and Cmax,ss were within the 0.80 to 1.25 interval and therefore fulfilled bioequivalence criteria. The 90% confidence interval for Cmax,ss for MF for the QMF149 vs. monotherapy comparison was [1.13, 1.26]. Although no definitive data can be provided on the basis of the present study results, it is unlikely that the small observed differences in expsoure are clinically meaningful. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated. CONCLUSIONS: The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC0-24h,ss and Cmax,ss for both indacaterol and mometasone furoate, indicating an absence of clinically relevant PK or biopharmaceutical interactions. These data support further development of QMF149 without dose adjustment.
RCT Entities:
PURPOSE:QMF149 is a fixed-dose combination of the long-acting β2 agonist, indacaterol and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic (PK) and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler(®) device, either alone or in a free or fixed combination (QMF149) in healthy adult subjects. METHODS: In this randomized, open-label, four-way crossover study, subjects were randomized to receive indacaterol acetate 150 μg, mometasone furoate 320 μg, alone and as free combination of the individual components, or QMF149 (indacaterol acetate 150 μg/mometasone furoate 320 μg) once daily for 14 days in each period, followed by a 7-day washout between periods. PK profiles were characterized on Day 14 up to 168 h post-dose. RESULTS:Indacaterol AUC0-24h,ss and Cmax,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC0-24h,ss and Cmax,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], higher, respectively than mometasone furoate monotherapy. The majority (three of four comparisons between QMF149 and monotherapy) of the 90% confidence intervals of the between-treatment ratios for AUC0-24h,ss and Cmax,ss were within the 0.80 to 1.25 interval and therefore fulfilled bioequivalence criteria. The 90% confidence interval for Cmax,ss for MF for the QMF149 vs. monotherapy comparison was [1.13, 1.26]. Although no definitive data can be provided on the basis of the present study results, it is unlikely that the small observed differences in expsoure are clinically meaningful. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated. CONCLUSIONS: The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC0-24h,ss and Cmax,ss for both indacaterol and mometasone furoate, indicating an absence of clinically relevant PK or biopharmaceutical interactions. These data support further development of QMF149 without dose adjustment.
Authors: Kai Michael Beeh; Anne-Marie Kirsten; Ana-Maria Tanase; Alexia Richard; Weihua Cao; Bettina Hederer; Jutta Beier; Oliver Kornmann; Richard N van Zyl-Smit Journal: Int J Chron Obstruct Pulmon Dis Date: 2018-12-06