Effects of activated factor X inhibitor,JTV-803, in a pig model of hemodialysis

JTV-803 (4-[(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl]-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate), a specific inhibitor of factor Xa, was evaluated in a pig hemodialysis model with ligation of renal arteries. In this model, JTV-803 administered into the dialysis circuit showed an anticoagulant effect (prolongation of dialysis time) at doses of 0.3 mg/kg+0.3, 1.0 and 3.0 mg/kg/h. The prolongation of dialysis time in the 0.3 mg/kg+1.0 mg/kg/h JTV-803 group was comparable to that in the 15 U/kg+7.5 U/kg/h heparin group. The plasma concentrations of JTV-803 following 0.3 mg/kg+1.0 mg/kg/h infusion of the drug into the dialysis circuit was 500 ng/ml or less, and prothrombin time was 1.5-fold or less than the pretreatment value. JTV-803 was removed by passing the blood through a dialyzer, resulting in a clearance rate of 53.4–81.8%. After the end of dialysis, plasma concentrations of JTV-803 decreased rapidly with time. These results suggest that human factor Xa inhibitor JTV-803 may have good potential as an antithrombotic agent during hemodialysis, with lower likelihood of bleeding after the end of dialysis.