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J.Health Sci., 49(5), 368-378, 2003
Evaluation of a New Blood Coagulation Factor Xa Inhibitor, KFA-1411, as an Anticoagulant in a Cynomolgus Monkey Hemodialysis Model: Parameters Suitable for Monitoring Anticoagulant Activities
Kiyoto Hara,*, a Toshiki Honma,b Yuji Hoyano,b Takashi Koizumi,a Masahiko Uchida,b Satoshi Akahane,b Masami Kojima,a and Masuo Akahanea
aPharmacology Research Laboratory and bDiscovery Research Laboratory, Research & Development, Kissei Pharmaceutical Co., Ltd. 4365-1, Kashiwabara Hotaka, Minamiazumi, Nagano 399-8304, Japan
A Cynomolgus monkey hemodialysis model was used to evaluate the efficacy of a new factor Xa (FXa) inhibitor as an anticoagulant for hemodialysis. We tested the selective FXa inhibitor KFA-1411, using doses of 0.15 mg/kg/hr, 0.3 mg/kg/hr, and 0.6 mg/kg/hr by continuous infusion in combination with a single loading-dose at the start. As a reference control, dalteparin, which is a low-molecular-weight heparin, was used at a dose of 20 IU/kg/hr plus 30 IU/kg single loading. As a monitoring method for KFA-1411, clotting time was measured in blood samples obtained from the body (systemic) and from the extracorporeal circulation (in-circuit). At KFA-1411 doses of 0.3 mg/kg/hr and 0.6 mg/kg/hr hemodialysis was maintained with essentially no change in the intra-bloodline pressure in the extracorporeal circulation. With dalteparin, the pressure increased almost to the upper limit (set at 250 mmHg). The clot-deposition score measured, after testoration of normal circulation, in the dialyzer and air-trap chamber in the extracorporeal circulation was improved in a dose-dependent manner in the KFA-1411 groups. There were no large differences between humans and Cynomolgus monkeys in the in vitro plasma anticoagulant activities of KFA-1411 and dalteparin. These results indicate that this selective FXa inhibitor could be used as an anticoagulant for hemodialysis. Both activated partial thromboplastin time (APTT) and prothrombin time (PT) can be used to monitor the anticoagulant activity in the extracorporeal circulation, and a drug dose that has sufficient anticoagulant efficacy for hemodialysis will prolong in-circuit-APTT about 2 times and in-circuit-PT about 3 times compared to normal.
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