title: A Two-Period Open-Label, Single-Dose Crossover Study in Healthy Volunteers to Evaluate the Drug-Drug Interaction Between Cimetidine and Inhaled Extrafine CHF 5993.
abstract: OBJECTIVE
  CHF 5993 is an extrafine 'triple therapy' combination of the long-acting muscarinic antagonist glycopyrronium bromide (GB), the long-acting β2-agonist formoterol fumarate (FF), and the inhaled corticosteroid beclometasone dipropionate (BDP). It is in development for chronic obstructive pulmonary disease and asthma delivered via pressurised metered-dose inhaler.
  
  
  METHODS
  This two-period, open-label, crossover study examined the drug-drug interaction of CHF 5993 and cimetidine. In one period, subjects received cimetidine 800 mg twice daily for 6 days; on the fourth day they also received CHF 5993 (BDP/FF/GB 400/24/100 µg). In the other, they received CHF 5993 alone. Primary objective was to compare the area under the plasma concentration-time curve from time 0 to last quantifiable concentration (AUC0-t) of GB, with and without cimetidine. Secondary endpoints included GB AUC0-12h, maximum concentration (Cmax), time to Cmax(tmax), elimination half-life (t½) and urinary excretion. Pharmacokinetic parameters of BDP, beclometasone-17-monopropionate (B17MP; active metabolite of BDP) and formoterol were also evaluated.
  
  
  RESULTS
  Twenty-six subjects were randomised; 25 completed. Co-administration of CHF 5993 and cimetidine resulted in small, statistically significant increases in GB AUC0-t, AUC0-12hand Cmaxvs CHF 5993 (ratios 1.16, 1.21 and 1.26, respectively); t½, tmaxand urinary excretion were unaffected. There were small, statistically significant increases in formoterol AUC0-t, AUC0-24hand t½following co-administration of cimetidine and CHF 5993; urinary excretion was unaffected. There were no significant differences for either BDP or B17MP. There were few adverse events (AEs), and no serious AEs.
  
  
  CONCLUSIONS
  Overall, this study indicates that there is no clinically relevant drug-drug interaction between CHF 5993 and cimetidine.
authors.affiliation: Global Clinical Development, Chiesi Farmaceutici SpA, Largo Belloli 11/A, 43122, Parma, Italy. F.Mariotti@chiesi.com.
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Mariotti
authors.affiliation: Global Clinical Development, Chiesi Farmaceutici SpA, Largo Belloli 11/A, 43122, Parma, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Ciurlia
authors.affiliation: Global Clinical Development, Chiesi Farmaceutici SpA, Largo Belloli 11/A, 43122, Parma, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Spaccapelo
authors.affiliation: Global Clinical Development, Chiesi Farmaceutici SpA, Largo Belloli 11/A, 43122, Parma, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Muraro
authors.affiliation: Global Clinical Development, Chiesi Farmaceutici SpA, Largo Belloli 11/A, 43122, Parma, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Acerbi
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001507:Beclomethasone / Q000493:pharmacokinetics*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002927:Cimetidine / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D000068759:Formoterol Fumarate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006024:Glycopyrrolate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D010316:Particle Size; D055815:Young Adult
chemical_list: D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D004338:Drug Combinations; D018727:Muscarinic Antagonists; D002927:Cimetidine; D001507:Beclomethasone; D006024:Glycopyrrolate; D000068759:Formoterol Fumarate