title: Dose-ranging study of salmeterol using a novel fluticasone propionate/salmeterol multidose dry powder inhaler in patients with persistent asthma.
abstract: BACKGROUND
  New inhalation devices with improved lung delivery may allow the use of lower salmeterol doses for treatment of asthma.
  
  
  OBJECTIVE
  To determine the dose of salmeterol administered from a novel fluticasone propionate/salmeterol (FS) inhalation-driven, multidose dry powder inhaler (MDPI), which provides comparable efficacy and safety to FS dry powder inhaler (DPI).
  
  
  METHODS
  This double-blind, six-period crossover, dose-ranging study randomized 72 patients (ages ≥12 years; with persistent asthma and predose maximum forced expiratory volume in 1 second [FEV1] of 40-85% of the predicted normal) to treatment sequences (one dose per treatment), which consisted of FS MDPI 100/6.25, 100/12.5, 100/25, 100/50 μg; fluticasone propionate (Fp) MDPI 100 μg; and open-label FS DPI 100/50 μg. The primary efficacy variable was the baseline-adjusted FEV1 area under the curve over 12 hours after the dose (AUC0-12). Pharmacokinetics and tolerability were also assessed.
  
  
  RESULTS
  FEV1 AUC0-12 was significantly higher with all FS MDPI doses and FS DPI versus Fp MDPI (p < 0.0001), and with FS MDPI 100/50 μg versus FS DPI (least squares [LS] mean, 57.88 mL; p = 0.0017). FEV1 AUC0-12 trended toward higher efficacy with FS MDPI 100/25 μg (LS mean, 34.14 mL; p = 0.0624) and was comparable with FS MDPI 100/12.5 μg (LS mean, 3.42 mL; p = 0.8503) versus FS DPI. Salmeterol area under the plasma concentration-versus-time curve from time 0 to the time of the last measurable concentration (AUC0-t) for FS MDPI 100/12.5 μg and 100/25 μg was lower versus FS DPI 100/50 μg; AUC0-t for FS MDPI 100/50 μg was higher than FS DPI 100/50 μg. All FS MDPI doses were generally well tolerated.
  
  
  CONCLUSIONS
  All FS MDPI doses produced greater efficacy versus Fp MDPI. FS MDPI 100/12.5 μg demonstrated similar efficacy to FS DPI 100/50 μg with less salmeterol exposure. Clinicaltrials.gov NCT02139644, NCT02175771, and NCT02141854.
authors.affiliation: Northeast Medical Research Associates, North Dartmouth, MA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Miller
authors.forename: Gloria
authors.initials: G
authors.lastname: Yiu
authors.forename: Edward T
authors.initials: ET
authors.lastname: Hellriegel
authors.forename: Jonathan
authors.initials: J
authors.lastname: Steinfeld
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D058995:Dry Powder Inhalers; D005260:Female; D000068297:Fluticasone-Salmeterol Drug Combination / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D012129:Respiratory Function Tests; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001993:Bronchodilator Agents; D000068297:Fluticasone-Salmeterol Drug Combination