title: Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.
abstract: BACKGROUND
  Drug-drug interactions with warfarin are common with potentially harmful consequences. Preclinical in vitro studies suggest that fesoterodine or 5-hydroxymethyl tolterodine are not likely to affect warfarin metabolism, but a lack of interaction has not been demonstrated in a clinical study.
  
  
  CONCLUSIONS
  This study shows that the pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg, and that co-administration of warfarin 25 mg and fesoterodine 8 mg is safe and well tolerated.
  
  
  OBJECTIVE
  To confirm the lack of an interaction of fesoterodine 8 mg with warfarin pharmacokinetics and pharmacodynamics in healthy adults.
  
  
  METHODS
  In this open-label, two-treatment, crossover study, subjects (n= 14) aged 20-41 years with normal prothrombin time (PT) and International Normalized Ratio (INR) were randomized to receive a single dose of warfarin 25 mg alone in one period and fesoterodine 8 mg once daily on days 1-9 with a single dose of warfarin 25 mg co-administered on day 3 in the other period. There was a 10-day washout between treatments. Pharmacokinetic endpoints were area under the plasma concentration-time curve from time 0 to infinity (AUC(0,∞)), maximum plasma concentration (C(max)), AUC from time 0 to the time of the last quantifiable concentration (AUC(0,last)), time to C(max) (t(max) ), and half-life (t(1/2)) for S- and R-warfarin. Pharmacodynamic endpoints were area under the INR-time curve (AUC(INR) ), maximum INR (INR(max)), area under the PT-time curve (AUC(PT)) and maximum PT (PT(max)).
  
  
  RESULTS
  Across all pharmacokinetic and pharmacodynamic comparisons, the point estimates of treatment ratio (warfarin co-administered with fesoterodine vs. warfarin alone) were 92-100%. The 90% confidence intervals for the ratios of the adjusted geometric means were contained within (80%, 125%). There were no clinically relevant changes in laboratory tests, vital signs or ECG recordings.
  
  
  CONCLUSIONS
  The pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg. Concomitant administration of fesoterodine and warfarin was well tolerated.
authors.affiliation: Pfizer Inc., New York, NY, USA. bimal.k.malhotra@pfizer.com
authors.forename: Bimal
authors.initials: B
authors.lastname: Malhotra
authors.forename: Christine
authors.initials: C
authors.lastname: Alvey
authors.forename: Jason
authors.initials: J
authors.lastname: Gong
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Li
authors.forename: Gregory
authors.initials: G
authors.lastname: Duczynski
authors.forename: Kuan
authors.initials: K
authors.lastname: Gandelman
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001682:Biological Availability; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D011517:Prothrombin Time; D014859:Warfarin / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D001559:Benzhydryl Compounds; D018727:Muscarinic Antagonists; D014859:Warfarin; C526675:fesoterodine