title: Influence of renal and hepatic impairment on the pharmacokinetic and pharmacodynamic properties and tolerability of fluticasone furoate and vilanterol in combination.
abstract: BACKGROUND
  Renal and hepatic disease may lead to alterations in drug absorption, distribution, and elimination, and, therefore, the potential effect of renal and hepatic impairment should be investigated in drugs under development.
  
  
  OBJECTIVE
  To assess the effects of renal and hepatic impairment on the pharmacokinetic and pharmacodynamic properties and tolerability of fluticasone furoate/vilanterol (FF/VI) administered in combination.
  
  
  METHODS
  Two open-label, parallel-group studies were conducted. Eligible study participants included adults with severe renal impairment (CrCl <30 mL/min) and those with mild, moderate, or severe hepatic impairment (by Child-Pugh classification). Patients were matched with healthy subjects. Participants received 7 days of inhaled FF/VI 200/25 or 100/12.5 μg (severe hepatic impairment only) once daily in the morning. Lack of effect was defined as an upper 90% confidence limit of the C(max) and AUC geometric mean impaired:healthy ratios (GMRs) of <2.
  
  
  RESULTS
  Study participants included patients with severe renal impairment (n = 9) or with mild (n = 9), moderate (n = 9), or severe (n = 8) hepatic impairment, together with matched healthy subjects (n = 9 per study). Lack of effect of severe renal impairment was demonstrated with FF (GMRs [90% CI]: C(max), 0.96 [0.57-1.61]; AUC(0-24), 0.91 [0.60-1.38]) and VI (C(max), 0.70 [0.49-1.00]; AUC(0-24), 1.56 [1.27-1.92]). Day-7 dose-normalized FF AUC(0-24) was greater in the groups with mild, moderate, and severe hepatic impairment than in healthy subjects (GMRs [90% CI]: 1.34 [0.82-2.20], 1.83 [1.11-2.99], and 1.75 [1.05-2.91], respectively); lack of effect was not demonstrated. There was no effect of hepatic impairment on dose-normalized VI C(max) or AUC(0-24). Apart from reduced serum cortisol weighted mean (0-24 hour) in patients with moderate hepatic impairment (34% reduction [90% CI, 11%-51%] compared with healthy subjects), there was no evidence of a difference in heart rate, serum potassium, or 24-hour serum cortisol between patients with severe renal impairment of any hepatic impairment and healthy subjects. No safety concerns were identified in any of the groups with impairment or their matched healthy controls.
  
  
  CONCLUSIONS
  Severe renal impairment had no apparent clinically relevant effects on the pharmacokinetic or pharmacodynamic properties or tolerability of FF/VI. Hepatic impairment had no apparent effect on VI systemic exposure but increased FF exposure. Fluticasone furoate was associated with reduced serum cortisol in patients with moderate hepatic impairment. These data suggest that caution should be exercised when prescribing FF/VI in patients with moderate or severe hepatic impairment due to a risk for unwanted systemic corticosteroid effects associated with increased FF systemic exposure. Clinicaltrials.gov identifiers: NCT01266941 and NCT01266980.
authors.affiliation: GlaxoSmithKline, Stevenage, United Kingdom. ann.allen@gsk.com
authors.forename: Ann
authors.initials: A
authors.lastname: Allen
authors.forename: Angela
authors.initials: A
authors.lastname: Davis
authors.forename: Kelly
authors.initials: K
authors.lastname: Hardes
authors.forename: Lee
authors.initials: L
authors.lastname: Tombs
authors.forename: Rodger
authors.initials: R
authors.lastname: Kempsford
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000730:Androstadienes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001592:Benzyl Alcohols / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D016022:Case-Control Studies; D002722:Chlorobenzenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D048550:Hepatic Insufficiency / Q000503:physiopathology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000503:physiopathology*; D012720:Severity of Illness Index
chemical_list: D000730:Androstadienes; D001592:Benzyl Alcohols; D002722:Chlorobenzenes; D004338:Drug Combinations; C550468:vilanterol; C523187:fluticasone furoate; D006854:Hydrocortisone