title: Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects.
abstract: OBJECTIVE
  To investigate the influence of nonvalvular atrial fibrillation (NVAF) on the pharmacokinetic (PK) properties of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran.
  
  
  METHODS
  In an open study, 12 patients with persistent NVAF and 12 age- and gender-matched, healthy control subjects received a 10-min intravenous (i.v.) infusion of 2.66 mg melagatran followed by oral ximelagatran, 36 mg twice daily, for the subsequent five study days. Plasma and urine samples for PK analyses were collected after i.v. and single and repeated oral dosing.
  
  
  RESULTS
  The oral absorption of ximelagatran was rapid, and maximum plasma concentrations of ximelagatran (Cmax) were achieved at about 1 h post-dosing. There were no differences between NVAF patients and controls for the area under the plasma concentration versus time curve, Cmax, half-life (t1/2), or bioavailability (F) of melagatran after oral dosing with ximelagatran. The Cmax of melagatran, formed by the rapid bioconversion of ximelagatran, occurred approximately 3 h post-dosing. The geometric means of the t1/2 for melagatran were 4.0 h and 4.2 h for the first and last doses, respectively, in patients, and 3.5 h and 3.7 h, respectively, in controls. Geometric means of F of melagatran following oral administration of ximelagatran were 22% and 24% for the first and last doses, respectively, in patients and 21% and 23%, respectively, in controls. Approximately 80% of the i.v. dose of melagatran was excreted in urine in patients and in controls.
  
  
  CONCLUSIONS
  The PK properties of oral ximelagatran and i.v. melagatran in elderly patients with NVAF are consistent with those in matched, healthy controls.
authors.affiliation: Department of Clinical Pharmacology, Allgemeines Krankenhaus Wien, University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Wolzt
authors.forename: Maria
authors.initials: M
authors.lastname: Wollbratt
authors.forename: Mia
authors.initials: M
authors.lastname: Svensson
authors.forename: Karin
authors.initials: K
authors.lastname: Wåhlander
authors.forename: Margaretha
authors.initials: M
authors.lastname: Grind
authors.forename: Ulf G
authors.initials: UG
authors.lastname: Eriksson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism*; D019540:Area Under Curve; D001281:Atrial Fibrillation / Q000097:blood / Q000378:metabolism* / Q000652:urine; D001384:Azetidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001596:Benzylamines; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D001384:Azetidines; D001596:Benzylamines; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin; D005998:Glycine