title: Effects of moderate hepatic impairment on the pharmacokinetic properties and tolerability of umeclidinium and vilanterol in inhalational umeclidinium monotherapy and umeclidinium/vilanterol combination therapy: an open-label, nonrandomized study.
abstract: BACKGROUND
  The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a monotherapy, and in combination with the long-acting β2-agonist vilanterol (VI), as a once-daily inhaled maintenance bronchodilator therapy for chronic obstructive pulmonary disease in the US and EU; they are not indicated for the treatment of asthma. Preclinical and clinical data suggest that UMEC and VI are predominantly eliminated by the liver.
  
  
  OBJECTIVE
  The objectives of the study were to evaluate the effects of moderate hepatic impairment on the plasma and urinary pharmacokinetic properties of each drug, and on the tolerability of inhalational UMEC/VI 125/25 µg and UMEC 125 µg.
  
  
  METHODS
  This open-label, nonrandomized study was conducted in patients with moderate hepatic impairment (Child-Pugh score, 7-9) and in healthy volunteers (control). Patients and volunteers were administered a single dose of UMEC/VI 125/25 µg, and, after a 7- to 14-day washout period, repeat-dose UMEC 125 µg once daily for 7 days. Primary end points were the plasma pharmacokinetic properties of single- and repeat-dose UMEC and VI. Secondary end points were the urinary pharmacokinetic properties of UMEC, and the tolerability of each treatment.
  
  
  RESULTS
  All 18 enrolled patients and volunteers (12 men, 6 women; mean age, 53.6 years) completed the study. Mean systemic exposures of UMEC and VI were similar or numerically lower in patients with moderate hepatic impairment compared with those in healthy volunteers, but the differences were not clinically significant. UMEC accumulations with 7-day dosing of UMEC were similar between patients with moderate hepatic impairment and healthy volunteers. UMEC/VI 125/25 µg and UMEC 125 µg were well-tolerated, with no safety concerns identified.
  
  
  CONCLUSIONS
  The administration of UMEC/VI 125/25 µg or UMEC 125 µg in patients with moderate hepatic impairment did not result in clinically relevant increases in UMEC or VI exposures compared with those in healthy volunteers. Based on these findings, no dose adjustment for UMEC/VI or UMEC is warranted in patients with moderate hepatic impairment.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina. Electronic address: rashmi.s.mehta@gsk.com.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Mehta
authors.affiliation: GlaxoSmithKline, Stockley Park, Middlesex, United Kingdom.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hardes
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Dennis
authors.initials: D
authors.lastname: Kelleher
authors.affiliation: GlaxoSmithKline, Stockley Park, Middlesex, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Preece
authors.affiliation: Synergy, Slough, Berkshire, United Kingdom.
authors.forename: Lee
authors.initials: L
authors.lastname: Tombs
authors.affiliation: GlaxoSmithKline, Stockley Park, Middlesex, United Kingdom.
authors.forename: Noushin
authors.initials: N
authors.lastname: Brealey
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000368:Aged; D001592:Benzyl Alcohols / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016022:Case-Control Studies; D002722:Chlorobenzenes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000097:blood* / Q000652:urine*; D008297:Male; D008875:Middle Aged; D011812:Quinuclidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D001592:Benzyl Alcohols; D002722:Chlorobenzenes; D004338:Drug Combinations; C573971:GSK573719; D011812:Quinuclidines; C550468:vilanterol
keywords: GSK573719; chronic obstructive pulmonary disease; long-acting muscarinic antagonist; long-acting β(2)-agonist; umeclidinium; vilanterol