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

Abstract

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.

Effects on fibrin network porosity of anticoagulants with different modes of action and reversal by activated coagulation factor concentrate*

“…The present study aimed to investigate the effect on the fibrin network of the following drugs: (i) AR‐H067637 the active metabolite of the DTI AZD0837 (Deinum et al , 2009; Lip et al 2009; Pehrsson et al , 2010), (ii) apixaban, a DFXaI (Carreiro & Ansell, 2008; Shantsila & Lip, 2008), (iii) the indirect FXaI fondaparinux (Hirsh et al , 2008) and (iv) warfarin plasma at different International Normalized Ratio (INR) levels (Ansell et al , 2008). Finally, we studied the effect of FEIBA ® (Collet et al , 2000; Schulman & Bijsterveld, 2007) on fibrin network permeability in anticoagulant‐treated plasma samples.…”

Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability

“…Introduction of a carboxylic acid in the meta position of 1 , to give compound 2 , reduced both of these liabilities. Satisfactorily, this was accomplished with only a minor loss in functional in vitro anticoagulant potency in human plasma, as measured by the concentration required to double the activated partial thromboplastin time (APTT) and the in vivo efficacy in prevention of venous thrombosis in the rat caval vein thrombosis model (VT). Accordingly, compound 2 was somewhat less potent than 1 as an inhibitor of human thrombin in vitro (Table ).…”

“…13 C NMR (126 MHz, CDCl 3 ) δ 171. 6, 167.1, 165.7, 147.3, 138.4, 134.0, 130.5, 130.5, 128.9, 128.6, 122.9, 63.2, 54.7, 52.3, 47.8, 32.4, 31.1, 20.6, 17.5 (20). TBAF (674 mg, 2.14 mmol) was added to 19 (770 mg, 1.78 mmol) dissolved in THF (5 mL), and the mixture was stirred at rt for 6 h. The solvent was removed in vacuo, and the residue was redissolved in EtOAc (10 mL) then sequentially washed with aqueous 0.1 M HCl (3 × 15 H 2 O (3 × 15 mL), and brine (3 × 15 mL), dried (Na 2 SO 4 ), filtered, and concentrated in vacuo.…”

Exposure–response for biomarkers of anticoagulant effects by the oral direct thrombin inhibitor AZD0837 in patients with atrial fibrillation

“…It is rapidly metabolized via the metabolite AR-H069927 to AR-H067637, a selective and reversible direct thrombin inhibitor [4][5][6]. The oral bioavailability of AZD0837 was 22-52% in healthy subjects given single ascending doses (range 15 to 750 mg) and the half-life of AR-H067637 was 9-14 h [5].…”

“…AZD0837 is a novel oral anticoagulant that has been investigated in phase II studies for prevention of stroke and systemic embolic events in patients with atrial fibrillation (AF) [1][2][3]. It is rapidly metabolized via the metabolite AR-H069927 to AR-H067637, a selective and reversible direct thrombin inhibitor [4][5][6]. The oral bioavailability of AZD0837 was 22-52% in healthy subjects given single ascending doses (range 15 to 750 mg) and the half-life of AR-H067637 was 9-14 h [5].…”