title: Pharmacokinetics of indacaterol and mometasone furoate delivered alone or in a free or fixed dose combination in healthy subjects.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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: Drug Metabolism and Pharmacokinetics, Clinical Pharmacokinetics/Pharmacodynamics, Novartis Institutes for BioMedical Research, Cambridge, MA, USA. Electronic address: soniya.vaidya@novartis.com.
authors: Soniya S
authors: SS
authors: Vaidya
authors: Translational Medicine, Novartis Institutes for BioMedical Research, Horsham, UK.
authors: Sanjeev
authors: S
authors: Khindri
authors: Translational Medicine, Novartis Institutes for BioMedical Research, Horsham, UK.
authors: Nicole
authors: N
authors: Calder
authors: Integrated Information Sciences, Novartis Healthcare Pvt. Ltd., Hyderabad, India.
authors: Surendra
authors: S
authors: Machineni
authors: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Hisanori
authors: H
authors: Hara
authors: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors: Tapan
authors: T
authors: Majumdar
authors: Simbec Research Ltd., Merthyr Tydfil, UK.
authors: Salvatore
authors: S
authors: Febbraro
authors: Early Phase Clinical Unit, PAREXEL, Berlin, Germany.
authors: Rainard
authors: R
authors: Fuhr
authors: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Ralph
authors: R
authors: Woessner
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D000068656:Mometasone Furoate / Q000008:administration & dosage / Q000493:pharmacokinetics; D011244:Pregnadienediols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D004338:Drug Combinations; D007189:Indans; D011244:Pregnadienediols; C000600413:QMF149; D015363:Quinolones; D000068656:Mometasone Furoate; C510790:indacaterol
keywords: Biopharmaceutical interaction; Indacaterol; Mometasone furoate; Pharmacokinetics; QMF149