title: Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions.
abstract: BACKGROUND
  Ximelagatran is an oral direct thrombin inhibitor currently in clinical development for the prevention and treatment of thromboembolic disorders. After oral administration, ximelagatran is rapidly absorbed and extensively bioconverted, via two intermediates (ethyl-melagatran and hydroxy-melagatran), to its active form, melagatran. In vitro studies have shown no evidence for involvement of cytochrome P450 (CYP) enzymes in either the bioactivation or the elimination of melagatran.
  
  
  OBJECTIVE
  To investigate the potential of ximelagatran, the intermediates ethyl-melagatran and hydroxy-melagatran, and melagatran to inhibit the CYP system in vitro and in vivo, and the influence of three CYP substrates on the pharmacokinetics of melagatran in vivo.
  
  
  METHODS
  The CYP inhibitory properties of ximelagatran, the intermediates and melagatran were tested in vitro by two different methods, using heterologously expressed enzymes or human liver microsomes. Diclofenac (CYP2C9), diazepam (CYP2C19) and nifedipine (CYP3A4) were chosen for coadministration with ximelagatran in healthy volunteers. Subjects received oral ximelagatran 24mg and/or diclofenac 50mg, a 10-minute intravenous infusion of diazepam 0.1 mg/kg, or nifedipine 60mg. The plasma pharmacokinetics of melagatran, diclofenac, diazepam, N-desmethyl-diazepam and nifedipine were determined when administered alone and in combination with ximelagatran.
  
  
  RESULTS
  No inhibition, or only minor inhibition, of CYP enzymes by ximelagatran, the intermediates or melagatran was shown in the in vitro studies, suggesting that ximelagatran would not cause CYP-mediated drug-drug interactions in vivo. This result was confirmed in the clinical studies. There were no statistically significant differences in the pharmacokinetics of diclofenac, diazepam and nifedipine on coadministration with ximelagatran. Moreover, there were no statistically significant differences in the pharmacokinetics of melagatran when ximelagatran was administered alone or in combination with diclofenac, diazepam or nifedipine.
  
  
  CONCLUSIONS
  As ximelagatran did not exert a significant effect on the hepatic CYP isoenzymes responsible for the metabolism of diclofenac, diazepam and nifedipine, it is reasonable to expect that it would have no effect on the metabolism of other drugs metabolised by these isoenzymes. Furthermore, the pharmacokinetics of melagatran after oral administration of ximelagatran are not expected to be altered by inhibition or induction of CYP2C9, CYP2C19 or CYP3A4. Together, the in vitro and in vivo studies indicate that metabolic drug-drug interactions involving the major human CYP enzymes should not be expected with ximelagatran.
authors.affiliation: Experimental Medicine, AstraZeneca R&D, Mölndal, Sweden. eva.bredberg@astrazeneca.com
authors.forename: Eva
authors.initials: E
authors.lastname: Bredberg
authors.forename: Tommy B
authors.initials: TB
authors.lastname: Andersson
authors.forename: Lars
authors.initials: L
authors.lastname: Frison
authors.forename: Annelie
authors.initials: A
authors.lastname: Thuresson
authors.forename: Susanne
authors.initials: S
authors.lastname: Johansson
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksson-Lepkowska
authors.forename: Marita
authors.initials: M
authors.lastname: Larsson
authors.forename: Ulf G
authors.initials: UG
authors.lastname: Eriksson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000578:Amidines / Q000097:blood; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001384:Azetidines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001596:Benzylamines; D018592:Cross-Over Studies; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D003975:Diazepam / Q000097:blood; D004008:Diclofenac / Q000097:blood; D004347:Drug Interactions; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood; D006801:Humans; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D009543:Nifedipine / Q000097:blood; D003708:Nordazepam / Q000097:blood; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000578:Amidines; D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D065607:Cytochrome P-450 Enzyme Inhibitors; C479417:N-hydroxymelagatran; D011355:Prodrugs; C479418:ethyl melagatran; D004008:Diclofenac; C109573:melagatran; C426686:ximelagatran; D003708:Nordazepam; D003577:Cytochrome P-450 Enzyme System; D013917:Thrombin; D009543:Nifedipine; D003975:Diazepam; D005998:Glycine