Pharmacokinetics and safety of a novel recombinant soluble human thrombomodulin, ART-123, in healthy male volunteers.

Abstract

The safety and pharmacokinetics of a novel recombinant soluble human thrombomodulin, ART-123 were evaluated in single- and multiple-dose studies involving 16 healthy male volunteers. ART-123 was administered by intravenous infusion over 2 hours. The single-dose study indicated that plasma ART-123 levels at doses of 0.03, 0.1, and 0.3 mg declined biexponentially and those half-lives were approximately 4 hours (t1/2 alpha) and 20 hours (t1/2 beta), respectively. The mean plasma peak concentration and area under the plasma concentration-time curves increased in proportion to the given doses. Mean urinary recovery within the first 48 hours was between 54.3% and 59.8% of dose. In the multiple-dose study, ART-123 was administered at a dose of 0.2 mg once daily for 3 days. ART-123 did not accumulate as judged from plasma concentrations and urinary recovery. There were no abnormal findings in objective symptoms and laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, bleeding time, coagulation and hemostatic parameters, blood chemistry, and urinalysis. There were no significant adverse reactions or abnormalities in physical and laboratory examinations that could definitely be attributed to the drug at a dose of 0.3 mg as a single administration and at a dose of 0.2 mg once daily for 3 days. These results indicate that ART-123 is safe at doses up to 0.2 mg once daily for 3 days and may have clinical application. Further studies are needed, however, to evaluate the safety and pharmacokinetics of ART-123 in the targeted population.