A repeat‐dose thorough QT study of inhaled fluticasone furoate/vilanterol combination in healthy subjects

• Published in: British journal of clinical pharmacology Vol. 77; no. 3; pp. 466 - 479
• Main Authors: Kempsford, Rodger, Allen, Ann, Kelly, Kathryn, Saggu, Parminder, Crim, Courtney
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2014
• Subjects: Administration, Inhalation; Adolescent; Adult; Aged; Androstadienes - administration & dosage; Androstadienes - adverse effects; Androstadienes - pharmacokinetics; Benzyl Alcohols - administration & dosage; Benzyl Alcohols - adverse effects; Benzyl Alcohols - pharmacokinetics; Bronchodilator Agents - administration & dosage; Bronchodilator Agents - adverse effects; Bronchodilator Agents - pharmacokinetics; Chlorobenzenes - administration & dosage; Chlorobenzenes - adverse effects; Chlorobenzenes - pharmacokinetics; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; fluticasone furoate; Glucocorticoids - administration & dosage; Glucocorticoids - adverse effects; Glucocorticoids - pharmacokinetics; healthy subjects; Healthy Volunteers; Heart Rate - drug effects; Humans; London; Long QT Syndrome - chemically induced; Long QT Syndrome - physiopathology; Male; Middle Aged; moxifloxacin; Pharmacodynamics; Risk Assessment; thorough QT; vilanterol; Young Adult; London; fluticasone furoate; thorough QT; healthy subjects; vilanterol; moxifloxacin
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.12243

Aims This study was designed as a thorough QT (TQT) study to evaluate the effects of fluticasone furoate (FF)/vilanterol (VI) in healthy subjects. Supportive data from a TQT study conducted with FF are also presented. Methods This was a randomized, placebo‐ and positive‐controlled, double‐dummy, double‐blind, four‐way crossover study, in which healthy subjects (n = 85) were randomized to 7 days of once‐daily treatment of FF/VI (200/25 or 800/100 μg) or placebo or single‐dose oral moxifloxacin (single‐blind, 400 mg). In the supportive TQT study, subjects (n = 40) were randomized to single‐dose inhaled FF (4000 μg), oral moxifloxacin (400 mg) or placebo. Results There was a lack of effect of FF/VI (200/25 μg) on QTcF (Fridericia's correction); all time‐matched mean differences from baseline relative to placebo (0–24 h) were <5 ms, with upper 90% confidence intervals (CI) of <10 ms. At 800/100 μg, FF/VI had no significant clinical effect on QTcF except at 30 min postdose when the 90% CI was >10 ms [mean (90% CI), 9.6 ms (7.2, 12.0)]. No effect on QTci (individually corrected) was observed at either strength of FF/VI, with mean time‐matched treatment differences <5 ms at all time points [upper 90% CIs <10 ms (0–24 h)]. Assay sensitivity was confirmed; moxifloxacin prolonged QTcF and QTci, with time‐matched mean differences from baseline relative to placebo of >10 ms (1–8 h postdose). Conclusions Repeat once‐daily dosing of FF/VI (200/25 μg), which is the highest therapeutic strength used in phase III studies, is not associated with QTc prolongation in healthy subjects. Supratherapeutic strength FF/VI (800/100 μg) demonstrated a small transient effect on QTcF but not on QTci.