Antithrombotic Effects of Concomitant Administration of BAY 59–7939 with Enoxaparin or Heparin - Interaction Study.

Abstract BAY 59–7939 is an oral, direct Factor Xa (FXa) inhibitor in development for the prevention and treatment of thromboembolic diseases. Current therapies include unfractionated heparin and low molecular weight heparins. Bridging therapy may be necessary when a patient receiving oral anticoagulation requires parenteral anticoagulants, or vice versa. The potential interaction, and feasibility of bridging therapy, using BAY 59–7939 and enoxaparin or heparin was investigated in a rat arteriovenous (AV)-shunt model. An AV shunt connected the right common carotid artery and the left jugular vein in anesthetized rats. A thrombogenic nylon thread was placed in the shunt, and the extracorporeal circulation was opened. After 15 minutes, the shunt was removed, the thread withdrawn, and the thrombus immediately weighed. Rats were randomized into two groups, and doses below the appropriate ED50 were chosen in order to demonstrate a possible additive effect in this model: group 1 received BAY 59–7939 (3 mg/kg p.o.) + saline s.c., enoxaparin (10 mg/kg s.c.) + solvent p.o., or BAY 59–7939 (3 mg/kg p.o.) + enoxaparin (10 mg/kg s.c.); group 2 received BAY 59–7939 (3 mg/kg p.o.) + saline i.v., heparin (15 IE/kg i.v.) + solvent p.o., or BAY 59–7939 (3 mg/kg p.o.) + heparin (15 IE/kg i.v.); control animals received the appropriate vehicles (saline + solvent). Blood samples were collected after thrombus removal: activated partial thromboplastin time (aPTT) was measured, and the inhibition of FXa activity after activation of FX by Russell's Viper Venom (RVV) was analyzed using a chromogenic substrate. Prothrombin time (PT) was also measured in group 2. As shown in the table, BAY 59–7939 and enoxaparin alone significantly inhibited thrombus formation (32% and 43%, respectively). Co-administration of BAY 59–7939 and enoxaparin resulted in an additive effect: thrombus formation was inhibited by 65% (p 13-fold with heparin alone; this was not affected by the addition of BAY 59–7939. The prolongation of PT achieved with BAY 59–7939 alone was not affected by the addition of heparin. Enoxaparin and heparin almost completely inhibited FXa; this effect was not reduced by the addition of BAY 59–7939. In conclusion, BAY 59–7939 did not reduce the antithrombotic efficacy of enoxaparin or heparin and vice versa. Furthermore, an additive effect on thrombus weight reduction was achieved when oral BAY 59–7939 (3 mg/kg) was combined with enoxaparin (10 mg/kg s.c.) or heparin (15 IE/kg i.v.). These animal data suggest that BAY 59–3979 and enoxaparin or heparin may be used sequentially if necessary, such as for bridging therapy. Thrombus weight reduction (% ± SEM) PT (X-fold prolongation ± SEM) aPTT (X-fold prolongation ± SEM) Inhibition of FXa (% ± SEM) Group 1 BAY 59–7939 (3 mg/kg p.o.) 32 ± 9* n.d. 1.1 ± 0.03* 68 ± 2*** Enoxaparin (10 mg/kg s.c.) 43 ± 9** n.d. 1.9 ± 0.2** 89 ± 1*** Combination 65 ± 3*** n.d. 2.9 ± 0.3** 93 ± 1*** Group 2 BAY 59–7939 (3 mg/kg p.o.) 25 ± 4*** 2.4 ± 0.2*** 1.2 ± 0.1 62 ± 3*** Heparin (15 IE/kg i.v.) 27 ± 3*** 1.1 ± 0.1 >13*** 96 ± 1*** Combination 49 ± 7*** 2.5 ± 0.5* >14*** 98 ± 1*** n.d.: not determined. *p