title: Oral direct thrombin inhibitors in clinical development.
abstract: Thrombin has long been a target for development of oral anticoagulants but it has been difficult to find synthetic inhibitors with a desirable combination of pharmacodynamic and pharmacokinetic properties. However, there are now two oral direct thrombin inhibitors (DTIs) in clinical development, ximelagatran (ExantaTM) and BIBR 1048. Both are prodrugs with two protecting groups that are eliminated after absorption from the gastrointestinal tract. Their main active substances, melagatran and BIBR 953, are both potent and selective DTIs. In experimental models of thrombosis, melagatran has been shown to have a shallower dose-response curve than warfarin and, therefore, a better separation between efficacy and bleeding. Oral bioavailability, measured as the plasma concentration of the active metabolite, seems to be higher for ximelagatran (20%) than for BIBR 1048 (estimated to 5%). BIBR 953 has a longer half-life (about 12 h) than does melagatran (3-5 h) after oral administration of BIBR 1048 and ximelagatran, respectively. Both melagatran and BIBR 953 are mainly eliminated via the renal route. The variability of the plasma concentration of melagatran after oral administration of ximelagatran is low. There are no clinically relevant interactions with food or cytochrome P450 metabolized drugs and ximelagatran. In clinical studies, ximelagatran has been administered in a twice-daily fixed-dose regimen without coagulation monitoring. Results of published clinical studies are encouraging, both with regard to efficacy and bleeding. Major indications in Phase III studies with ximelagatran are the prevention of venous thromboembolism (VTE) in hip and knee replacement surgery, treatment and long-term secondary prevention of VTE and prevention of stroke in patients with nonvalvular atrial fibrillation. It is anticipated that with a favourable outcome of the Phase III clinical studies new oral DTIs, with the oral fixed-dose regimen without routine coagulation monitoring, will ease the use of today's anticoagulant therapy.
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden. david.gustafsson@astrazeneca.com
authors.forename: D
authors.initials: D
authors.lastname: Gustafsson
mesh_terms: D000925:Anticoagulants / Q000627:therapeutic use*; D001384:Azetidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use; D001596:Benzylamines; D000069604:Dabigatran; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D011355:Prodrugs / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D020521:Stroke / Q000517:prevention & control; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000517:prevention & control*; D020246:Venous Thrombosis / Q000517:prevention & control; D014812:Vitamin K / Q000037:antagonists & inhibitors
chemical_list: D000925:Anticoagulants; D001384:Azetidines; C453961:BIBR 953; D001562:Benzimidazoles; D001596:Benzylamines; D011355:Prodrugs; D011725:Pyridines; D014812:Vitamin K; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin; D000069604:Dabigatran; D005998:Glycine