title: Effect of verapamil on systemic exposure and safety of umeclidinium and vilanterol: a randomized and open-label study.
abstract: BACKGROUND
  The combination of umeclidinium (UMEC), a long-acting muscarinic receptor antagonist, and vilanterol (VI), a selective long-acting β₂ agonist, is in development for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the pharmacokinetics, safety and tolerability, and pharmacodynamics of once-daily, inhaled UMEC and UMEC/VI when co-administered with oral verapamil, a moderate P-glycoprotein transporter and moderate cytochrome P450 3A4 (CYP3A4) inhibitor frequently used by patients with COPD and cardiovascular comorbidities.
  
  
  METHODS
  Subjects were randomized to one of two 13-day treatment regimens: UMEC 500 μg or UMEC 500 μg/VI 25 μg. All subjects received a single tablet containing 240 mg verapamil on each of days 9-13.
  
  
  RESULTS
  Repeat doses of UMEC and UMEC/VI in combination with and without verapamil were safe and well tolerated. There was no increase in systemic exposure of UMEC when administered in combination with VI compared to UMEC alone. UMEC maximum concentration was similar with or without verapamil; a moderate increase in UMEC area under the curve (approximately 1.4-fold) was observed with verapamil. Verapamil did not increase systemic exposure to VI following administration of the UMEC/VI combination.
  
  
  CONCLUSIONS
  Administration of UMEC and UMEC/VI combination was well tolerated and did not show clinically relevant increases in systemic exposure for either drug. The UMEC/VI combination is unlikely to have a clinically meaningful drug-drug interaction with moderate P-glycoprotein transporter and CYP3A4 inhibitor drugs.
authors.affiliation: Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. rashmi.s.mehta@gsk.com
authors.forename: Rashmi
authors.initials: R
authors.lastname: Mehta
authors.forename: Dennis
authors.initials: D
authors.lastname: Kelleher
authors.forename: Andrew
authors.initials: A
authors.lastname: Preece
authors.forename: Stephen
authors.initials: S
authors.lastname: Hughes
authors.forename: Glenn
authors.initials: G
authors.lastname: Crater
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D058666:Adrenergic beta-2 Receptor Agonists / Q000097:blood / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D001592:Benzyl Alcohols / Q000097:blood / Q000627:therapeutic use*; D002722:Chlorobenzenes / Q000097:blood / Q000627:therapeutic use*; D004338:Drug Combinations; D058995:Dry Powder Inhalers; D005260:Female; D006339:Heart Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000097:blood / Q000627:therapeutic use*; D011188:Potassium / Q000097:blood; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D011812:Quinuclidines / Q000097:blood / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000097:blood / Q000627:therapeutic use*; D014700:Verapamil / Q000097:blood / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001592:Benzyl Alcohols; D002722:Chlorobenzenes; D004338:Drug Combinations; C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D014665:Vasodilator Agents; C550468:vilanterol; D014700:Verapamil; D011188:Potassium
keywords: long-acting muscarinic antagonist; long-acting β2 agonist; umeclidinium; verapamil; vilanterol