Background: Anticoagulants are often given for extended periods of time to patients at high risk for venous thromboembolism, such as after orthopedic surgery. Daily subcutaneous (sc) injections can be inconvenient to the patient. A long-acting anticoagulant requiring less frequent dosing could make treatment more acceptable. Thrombomodulin is a natural anticoagulant that activates protein C, which leads to inactivation of factor (F)Va and FVIIIa and decreased thrombin formation. Recombinant human thrombomodulin is a novel anticoagulant with a long half-life in animal models.
Methods and results: This phase I study examined pharmacokinetics, pharmacodynamics, and safety of recombinant human soluble thrombomodulin (ART-123) after administration of doses between 0.02 and 0.06 mg kg(-1) body weight intravenously (iv), and between 0.02 and 0.45 mg kg(-1) sc in 55 healthy volunteers. The plasma half-life was 2-3 days after sc injection of various single doses. Plasma ART-123 levels estimated to be needed for prevention of thrombus formation in humans were maintained for at least 6 days after single sc injection of 0.30 and 0.45 mg kg(-1) ART-123. Antithrombotic activity with these doses was demonstrated by achieving prothrombinase inhibition of more than 80% for more than 6 days after administration. No major bleeding occurred. Pharmacodynamic modeling revealed that adequate antithrombotic ART-123 levels can be achieved for 6 days with one dose of 0.45 mg kg(-1) ART-123, and for 12 days with 2 doses of 0.30 mg kg(-1), given 5 days apart.
Conclusions: Recombinant human soluble thrombomodulin (ART-123) has a long half-life after sc injection and is well tolerated, making it a suitable agent to be tested in clinical thromboprophylaxis trials.