title: The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjects.
abstract: OBJECTIVE
  To investigate the effects of the cytochrome P450 3A4 (CYP3A4) inhibitor ketoconazole on the pharmacokinetics (PK) and pharmacodynamics of fluticasone furoate (FF) and vilanterol trifenatate (VI).
  
  
  METHODS
  Two double-blind, randomized, placebo-controlled, two-way crossover studies in healthy subjects. In study 1, subjects received single doses of ketoconazole (400 mg) or placebo on days 1-6, with a single dose of inhaled VI (25 μg) on day 5. Pharmacodynamic and PK data were obtained up to 48 h following the VI dose. In study 2, subjects received once daily ketoconazole (400 mg) or placebo for 11 days, with FF/VI (200/25 μg) for the final 7 days. Pharmacodynamic and PK data were obtained up to 48 h following the day 11 dose.
  
  
  RESULTS
  In study 1, there was no effect of co-administration of ketoconazole and VI on pharmacodynamic or PK parameters. In study 2, co-administration of ketoconazole and FF/VI had no effect on 0-4 h maximal heart rate or minimal blood potassium {treatment difference [90% confidence interval (CI)] -0.6 beats min(-1) (-5.8, 4.5) and 0.04 mmol l(-1) (-0.03, 0.11), respectively}, whilst there was a 27% decrease in 24 h weighted mean serum cortisol [treatment ratio (90% CI) 0.73 (0.62, 0.86)]. Co-administration of ketoconazole increased [percentage change (90% CI)] FF area under the curve (0-24) and maximal plasma concentration by 36% (16, 59) and 33% (12, 58), respectively, and VI area under the curve (0-t') and maximal plasma concentration by 65% (38, 97) and 22% (8, 38), respectively.
  
  
  CONCLUSIONS
  Co-administration of FF/VI or VI with ketoconazole resulted in a less than twofold increase in systemic exposure to FF and VI. There was no increase in β-agonist systemic pharmacodynamic effects, while serum cortisol was decreased by 27%. Co-administration of FF/VI with strong CYP3A4 inhibitors has the potential to increase systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increase in the potential for adverse reactions.
authors.affiliation: GlaxoSmithKline R&D, Stevenage, Hertfordshire, SG1 2NY, UK. rodger.d.kempsford@gsk.com
authors.forename: Rodger
authors.initials: R
authors.lastname: Kempsford
authors.forename: Ann
authors.initials: A
authors.lastname: Allen
authors.forename: Joanne
authors.initials: J
authors.lastname: Bal
authors.forename: David
authors.initials: D
authors.lastname: Rubin
authors.forename: Lee
authors.initials: L
authors.lastname: Tombs
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000494:pharmacology*; D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000730:Androstadienes / Q000493:pharmacokinetics*; D001592:Benzyl Alcohols / Q000493:pharmacokinetics*; D001993:Bronchodilator Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D002722:Chlorobenzenes / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000730:Androstadienes; D001592:Benzyl Alcohols; D001993:Bronchodilator Agents; D002722:Chlorobenzenes; D065692:Cytochrome P-450 CYP3A Inhibitors; C550468:vilanterol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C523187:fluticasone furoate; D007654:Ketoconazole