title: Bioequivalence of ximelagatran, an oral direct thrombin inhibitor, as whole or crushed tablets or dissolved formulation.
abstract: OBJECTIVE
  To investigate whether crushed or dissolved tablets of the oral direct thrombin inhibitor ximelagatran are bioequivalent to whole tablet administration. Ximelagatran is currently under development for the prevention and treatment of thromboembolic disorders.
  
  
  METHODS
  This was an open-label, randomised, three-period, three-treatment crossover study in which 40 healthy volunteers (aged 20-33 years) received a single 36-mg dose of ximelagatran administered in three different ways: I swallowed whole, II crushed, mixed with applesauce and ingested and III dissolved in water and administered via nasogastric tube.
  
  
  RESULTS
  The plasma concentrations of ximelagatran, its intermediates and the active form melagatran were determined. Ximelagatran was rapidly absorbed and the bioavailability of melagatran was similar after the three different administrations, fulfilling the criteria for bioequivalence. The mean area under the plasma concentration-versus-time curve (AUC) of melagatran was 1.6 micromol.h/L (ratio 1.01 for treatment II/I and 0.97 for treatment III/I), the mean peak concentration (C(max)) was 0.3 micromol/L (ratio 1.04 for treatment II/I and 1.02 for treatment III/I) and the mean half-life (t(1/2)) was 2.8 h for all treatments. The time to C(max) (t(max)) was 2.2h for the whole tablet and approximately 0.5 h earlier when the tablet was crushed or dissolved (1.7-1.8 h), due to a more rapid absorption. The study drug was well tolerated as judged from the low incidence and type of adverse events reported.
  
  
  CONCLUSIONS
  The present study showed that the pharmacokinetics (AUC and C(max)) of melagatran were not significantly altered whether ximelagatran was given orally as a crushed tablet mixed with applesauce or dissolved in water and given via nasogastric tube.
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden. kajs-marie.schuetzer@astrazeneca.com
authors.forename: Kajs-Marie
authors.initials: KM
authors.lastname: Schützer
authors.forename: Ulrika
authors.initials: U
authors.lastname: Wall
authors.forename: Carina
authors.initials: C
authors.lastname: Lönnerstedt
authors.forename: Lis
authors.initials: L
authors.lastname: Ohlsson
authors.forename: Renli
authors.initials: R
authors.lastname: Teng
authors.forename: Troy C
authors.initials: TC
authors.lastname: Sarich
authors.forename: Ulf G
authors.initials: UG
authors.lastname: Eriksson
mesh_terms: D000328:Adult; D001384:Azetidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001596:Benzylamines; D018592:Cross-Over Studies; D004304:Dosage Forms; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male
chemical_list: D001384:Azetidines; D001596:Benzylamines; D004304:Dosage Forms; D005343:Fibrinolytic Agents; C426686:ximelagatran