Phase I study of a novel recombinant human soluble thrombomodulin, ART‐123

Abstract

Summary. 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.

The effect of aprotinin on activated protein C‐mediated downregulation of endogenous thrombin generation

“…(c. 31AE3 lg/ml) (Esmon, 2003), and therapeutic levels of rhsTM may reach 24 nmol/l (c. 1AE5 lg/ml) (Moll et al, 2004). Thus, the concentrations of rhsTM, 0AE75 and 3 lg/ml, in our experiments are within physiological and therapeutic thrombomodulin levels.…”

“…Plasma thrombomodulin levels below 23 ng/ml did not have any biological activity (Mohri et al, 1999;Moll et al, 2004), and may not represent functional thrombomodulin. In the microcirculation, endothelium-bound thrombomodulin is present at up to 500 nmol/l …”

Thrombomodulin Protects Endothelial Cells From a Calcineurin Inhibitor–Induced Cytotoxicity by Upregulation of Extracellular Signal–Regulated Kinase/Myeloid Leukemia Cell-1 Signaling

“…34 The present study used 30 to 100 ng/mL rTM, which was clinically relevant. Use of rTM could prevent and cure the potentially lethal complications, such as sinusoidal obstructive syndrome and transplantation-associated microangiopathy after hematopoietic stem cell transplantation, in which endothelial cell injury plays a pathophysiological role.…”

Pharmacokinetics of Recombinant Soluble Human Thrombomodulin in Subjects with Normal and Various Impaired Renal Function

“…The previous phase 1 studies in healthy subjects showed approximately 45-70% of thrombomodulin alfa administered intravenously was excreted in urine [1,6,7] and the remaining thrombomodulin alfa was cleared via non-renal pathways. CLtot of Severe Impairment and ESRD Groups decreased to 27.5% and 32.4% of CLtot of Healthy Group, hence the renal clearance of thrombomodulin alfa in these renal-impaired population was thought to be very minimal.…”

“…Repeated administration did not alter the pharmacokinetics (PK) of thrombomodulin alfa [1]. Thrombomodulin alfa is excreted primarily via the kidney, with approximately 45% to 70% of thrombomodulin alfa recovered in the urine following intravenous administration [1,6,7]. Two population pharmacokinetics (PPK) analyses were performed; one in a Japanese population [8] and the other in a non-Japanese population [5] which included subjects with various levels of renal impairment but excluded the population requiring hemodialysis.…”