Evaluation of AR-H067637, the active metabolite of the new direct thrombin inhibitor AZD0837, in models of venous and arterial thrombosis and bleeding in anaesthetised rats.
AZD0837, currently in clinical development, is a once-daily oral anticoagulant that is bioconverted to AR-H067637, a selective, reversible direct thrombin inhibitor (DTI). When developing a new DTI, the antithrombotic effects are commonly investigated in in vivo animal models; this report shows the effect of AR-H067637 in venous and arterial thrombosis and bleeding models in anaesthetised rats. Thrombus formation was induced by topical application of ferric chloride to the carotid artery or to the caval vein with partial stasis. Cutaneous incision bleeding time and muscle transection blood loss were assessed, with or without acetylsalicylic acid (ASA). Activated partial thromboplastin time (APTT), ecarin coagulation time (ECT) and thrombin coagulation time (TCT) were used as plasma biomarkers of anticoagulant effect. Dalteparin was used as a reference compound. AR-H067637, given by continuous infusion, displayed a dose-dependent antithrombotic effect, with 50% inhibition (IC50) of thrombus size in venous and arterial thrombosis models obtained at plasma concentrations of 0.13 μM and 0.55 μM, respectively, without increased bleeding. Dose-dependent increased bleeding and blood loss were seen at plasma concentrations ≥1 μM AR-H067637. At the highest AR-H067637 plasma concentration tested, bleeding time and blood loss increased two and four times the vehicle group. Addition of ASA moderately potentiated bleeding time and blood loss. APTT, ECT and TCT were dose-dependently prolonged. These studies demonstrate that the DTI AR-H067637 inhibits thrombus formation in rat venous and arterial thrombosis models with no or minor increases in bleeding.
Pehrsson
S
S
AstraZeneca R&D, Bioscience, SE 431 83 Mölndal, Sweden.
Johansson
K
K
Kjaer
M
M
Elg
M
M
D000578:Amidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000990:Antithrombin III; D000991:Antithrombins / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D001384:Azetidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D001777:Blood Coagulation / Q000187:drug effects*; D002712:Chlorides; D017985:Dalteparin / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005290:Ferric Compounds; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D006470:Hemorrhage / Q000139:chemically induced; D007262:Infusions, Intravenous; D008297:Male; D010314:Partial Thromboplastin Time; D010447:Peptide Hydrolases / Q000097:blood; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013918:Thrombin Time; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D020246:Venous Thrombosis / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*
C552153:AR-H067637; C551586:AZD 0837; D000578:Amidines; D000991:Antithrombins; D001384:Azetidines; D002712:Chlorides; D005290:Ferric Compounds; D005343:Fibrinolytic Agents; D011355:Prodrugs; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D010447:Peptide Hydrolases; D013917:Thrombin; D017985:Dalteparin; C024555:ferric chloride