title: Effect of cimetidine, a model drug for inhibition of the organic cation transport (OCT2/MATE1) in the kidney, on the pharmacokinetics of glycopyrronium.
abstract: OBJECTIVE
  Glycopyrronium (NVA237), a novel once-daily long-acting muscarinic antagonist (LAMA), has recently been approved for maintenance treatment of COPD. This study evaluated the effect of organic cation transporter inhibition on inhaled glycopyrronium disposition using cimetidine as a probe inhibitor.
  
  
  METHODS
  In this open-label, two-period, two-sequence, crossover study, 20 healthy subjects received two treatments. A single dose of 100 μg glycopyrronium was inhaled alone and on Day 4 of a 6-day treatment with oral cimetidine 800 mg b.i.d. Trough plasma concentrations of cimetidine were determined throughout cimetidine dosing. Plasma concentrations and urinary excretion of glycopyrronium were determined up to 72 hours post glycopyrronium dose. The primary pharmacokinetics (PK) parameters were plasma peak concentration (Cmax), AUC up to the last measured concentration (AUClast), and renal clearance (CLr) of glycopyrronium.
  
  
  RESULTS
  Cimetidine trough concentrations indicated that PK steady state of cimetidine was reached prior to single dose inhalation of glycopyrronium. Inhalation of glycopyrronium in the presence of cimetidine resulted in an increase in total systemic exposure (AUClast) of glycopyrronium by 22% (geometric mean ratio 1.22; 90% CI: 1.12 - 1.32). This exposure increase correlated with a slight decrease of 23% in CLr (geometric mean ratio 0.77; 90% CI: 0.70 - 0.85). Cmax was not affected. Both treatments were safe and well tolerated without any deaths or severe adverse events.
  
  
  CONCLUSIONS
  Based on the magnitude of the PK changes seen in this study, no relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport.
authors.forename: Swati
authors.initials: S
authors.lastname: Dumitras
authors.forename: Romain
authors.initials: R
authors.lastname: Sechaud
authors.forename: Anton
authors.initials: A
authors.lastname: Drollmann
authors.forename: Parasar
authors.initials: P
authors.lastname: Pal
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Vaidyanathan
authors.forename: Gian
authors.initials: G
authors.lastname: Camenisch
authors.forename: Guenther
authors.initials: G
authors.lastname: Kaiser
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002927:Cimetidine / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006024:Glycopyrrolate / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D055815:Young Adult
chemical_list: D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; D002927:Cimetidine; D006024:Glycopyrrolate