title: Safety, tolerability, pharmacodynamics and pharmacokinetics of umeclidinium and vilanterol alone and in combination: a randomized crossover trial.
abstract: Umeclidinium bromide (GSK573719; UMEC), a new long-acting muscarinic receptor antagonist (LAMA), is in development with vilanterol (GW642444; VI), a selective long-acting β(2) agonist (LABA), as a once-daily inhaled combination therapy for the treatment of chronic obstructive pulmonary disease (COPD). A single dose healthy volunteer study was conducted to assess the safety and tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of inhaled umeclidinium (500 µg) and vilanterol (50 µg) when administered separately and in combination using a novel dry powder inhaler (NDPI). Co-administration of single inhaled doses of umeclidinium and vilanterol to healthy Japanese subjects was well tolerated and not associated with meaningful changes in systemic exposure or PD effects compared with administration of either compound individually. Pharmacokinetic assessments showed rapid absorption for both drugs (Tmax = 5 min for both umeclidinium and vilanterol) followed by rapid elimination with median tlast of 4-5 h for umeclidinium and median tlast of 1.5-2.0 h for vilanterol. Assessments of pharmacokinetic interaction were inconclusive since for umeclidinium, Cmax following combination was higher than umeclidinium alone but not AUC whereas for vilanterol, AUC following combination was higher than vilanterol alone but not Cmax. There were no obvious trends observed between individual maximum supine heart rate and umeclidinium Cmax or vilanterol Cmax when delivered as umeclidinium 500 µg and vilanterol 50 µg combination or when delivered as umeclidinium or vilanterol alone.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT00976144.
authors.affiliation: Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America. dennis.l.kelleher@gsk.com
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kelleher
authors.forename: Rashmi S
authors.initials: RS
authors.lastname: Mehta
authors.forename: Bernadette M
authors.initials: BM
authors.lastname: Jean-Francois
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Preece
authors.forename: James
authors.initials: J
authors.lastname: Blowers
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Crater
authors.forename: Paul
authors.initials: P
authors.lastname: Thomas
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001592:Benzyl Alcohols / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D002722:Chlorobenzenes / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D058995:Dry Powder Inhalers / Q000295:instrumentation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D061214:Patient Safety; D011812:Quinuclidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001592:Benzyl Alcohols; D002722:Chlorobenzenes; C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines; C550468:vilanterol