title: Concentration-QT analysis of the randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects.
abstract: The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a once-daily monotherapy and in combination with the long-acting β2 agonist vilanterol (VI) for chronic obstructive pulmonary disease. The objective of this analysis was to assess the relationship between observed plasma UMEC and/or VI concentrations and QT interval corrected using Fridericia's correction (QTcF). 103 subjects were enrolled and 86 (83 %) completed the study. Subjects were randomized to 4 of 5 repeat-dose treatments (days 1-10: n = 77 subjects received placebo, n = 76 UMEC 500 µg, n = 78 UMEC/VI 125/25 µg, or n = 76 UMEC/VI 500/100 µg; day 10: n = 74 oral tablet moxifloxacin 400 mg [positive control]). The concentration-QTcF interval relationship was examined using nonlinear mixed-effects methods. For UMEC, predicted QTcF interval prolongation (at observed geometric mean of maximum plasma concentrations) was -2.38 ms (90 % prediction interval [PI] -3.82, -0.85) with UMEC 500 µg and -0.50 ms (90 % PI -0.80, -0.18) and -2.01 ms (90 % PI -3.22, -0.72) with UMEC/VI 125/25 µg and 500/100 µg, respectively. For VI, estimates were 5.89 ms (90 % PI 4.89, 6.91) and 7.23 ms (90 % PI 5.88, 8.55) with UMEC/VI 125/25 µg and 500/100 µg, respectively. Combined additive mean effects were estimated for UMEC/VI 125/25 µg (5.39 ms [90 % PI 4.40, 6.47]) and 500/100 µg (5.22 ms [90 % PI 3.72, 6.80]). The model-predicted decrease with UMEC and increase with UMEC/VI combination in QTcF interval suggest that the QT effect is likely attributable to VI. These model-predicted results support those of previously-published traditional statistical analyses.
authors.affiliation: Clinical Pharmacology Modeling Simulation, GSK, 5 Moore Drive, Research Triangle Park, NC, 27709, USA. rashmi.s.mehta@gsk.com.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Mehta
authors.affiliation: Quantitative Solutions, Menlo Park, CA, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Green
authors.affiliation: Clinical Pharmacology Modeling Simulation, GSK, King of Prussia, Philadelphia, PA, USA.
authors.forename: Bela
authors.initials: B
authors.lastname: Patel
authors.affiliation: Translational Medicine, Shire, Eysins, Switzerland.|Clinical Pharmacology, Head Oncology Modeling, Roche, Basel, Switzerland.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wagg
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000097:blood; D000328:Adult; D001592:Benzyl Alcohols / Q000008:administration & dosage* / Q000097:blood; D002722:Chlorobenzenes / Q000008:administration & dosage* / Q000097:blood; D018592:Cross-Over Studies; D004338:Drug Combinations; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage* / Q000097:blood; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D018727:Muscarinic Antagonists / Q000008:administration & dosage* / Q000097:blood; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D011812:Quinuclidines / Q000008:administration & dosage* / Q000097:blood; D013607:Tablets / Q000008:administration & dosage; D059005:Topoisomerase II Inhibitors / Q000008:administration & dosage* / Q000097:blood; D055815:Young Adult
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001592:Benzyl Alcohols; D002722:Chlorobenzenes; D004338:Drug Combinations; D024841:Fluoroquinolones; C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D013607:Tablets; D059005:Topoisomerase II Inhibitors; C550468:vilanterol; D000077266:Moxifloxacin
keywords: Chronic obstructive pulmonary disease; QT interval; Umeclidinium; Vilanterol