title: The effect of warfarin on the pharmacokinetics and pharmacodynamics of napsagatran in healthy male volunteers.
abstract: OBJECTIVE
  The effect of oral warfarin on the pharmacokinetics and pharmacodynamics of the synthetic direct thrombin inhibitor napsagatran was investigated.
  
  
  METHODS
  In an open, randomised, two-way crossover study, 12 healthy male volunteers were infused napsagatran (80 micrograms/min) for 48 h. Each subject was administered 25 mg warfarin (Coumadin) at the start of the infusion in either the first or second treatment period. Sampling was performed regularly over the treatment period and 24 h thereafter for measurement of plasma levels of napsagatran, activated partial thromboplastin time (APTT) and prothrombin time (PT).
  
  
  RESULTS
  The pharmacokinetic parameters of napsagatran were not significantly influenced by co-administration of warfarin. Napsagatran administration was followed by increases in APTT and PT. Co-administration of warfarin increased the AUEC (area under the effect curve) calculated for the period 0-48 h (corrected for baseline) for APTT by 45% (95% CI: 28-65%) and for PT by 438% (95% CI: 272-678%) compared to the treatment with napsagatran alone.
  
  
  CONCLUSIONS
  Warfarin has no effect on the pharmacokinetics of napsagatran, but has a marked influence on the pharmacodynamic parameters (APTT, PT) of napsagatran. In clinical practice, this interaction between the two compounds should be taken into account. The PT cannot be used to monitor the effect of oral anticoagulants during the switch from this group of direct thrombin inhibitors to full oral anticoagulant therapy.
authors.affiliation: Centre for Human Drug Research (CHDR), Zernikedreef 10, 2333 CL Leiden, The Netherlands. rf@chdr.nl
authors.forename: R A
authors.initials: RA
authors.lastname: Faaij
authors.forename: J M
authors.initials: JM
authors.lastname: van Griensven
authors.forename: R C
authors.initials: RC
authors.lastname: Schoemaker
authors.forename: T
authors.initials: T
authors.lastname: Goggin
authors.forename: A
authors.initials: A
authors.lastname: Guenzi
authors.forename: J M
authors.initials: JM
authors.lastname: Kroon
authors.forename: J
authors.initials: J
authors.lastname: Burggraaf
authors.forename: A F
authors.initials: AF
authors.lastname: Cohen
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000991:Antithrombins / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D018592:Cross-Over Studies; D006801:Humans; D008297:Male; D008954:Models, Biological; D009281:Naphthalenes / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010314:Partial Thromboplastin Time; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011517:Prothrombin Time; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D009281:Naphthalenes; D010880:Piperidines; D014859:Warfarin; C087198:napsagatran