Abstract
SummaryRecombinant human soluble thrombomodulin (ART-123) is a novel anticoagulant for patients with disseminated intravascular coagulation (DIC). It is widely used in clinical settings throughout Japan. Furthermore, a global Phase 3 study is currently being conducted. In healthy subjects, ART-123 is excreted mainly via the kidneys. Therefore, ART-123 dose decrease was recommended in DIC patients with severe renal dysfunction. However, the pharmacokinetics of ART-123 in DIC patients with severe acute renal dysfunction has not been elucidated. In an open-label, multicentre, prospective, clinical pharmacological study, we investigated the pharmacokinetics and safety of ART-123 upon repeated administration to DIC patients. ART-123 was administered to patients at a dose of 130 or 380 U/kg/day for six consecutive days. Plasma concentrations of ART-123 were measured at 21 time points until eight days after the final administration. Urinary excretion rates during the first 24 hours (h) were calculated. Patient renal functions were evaluated by measuring 24-h creatinine clearance (Ccr). Forty-three patients were enrolled in the present study. The urinary excretion rates of ART-123 correlated closely with 24-h Ccr. Total body clearance of ART-123 was also weakly related with 24-h Ccr. However, the plasma concentrations of ART-123 were not considerably different among patients with different renal function. Two patients had subcutaneous haemorrhage as an adverse event related to ART-123. In conclusion, plasma concentrations of ART-123 may not be different among patients with different renal functions. ART-123 was well tolerated in these patients.
Highlights
Thrombomodulin is a thrombin and protein C receptor on endothelial cell surface and plays an important role in the regulation of coagulation and the innate immune system [1]
We previously reported that the pharmacokinetic parameters of ART-123 in disseminated intravascular coagulation (DIC) patients with severe renal dysfunction were only slightly different from those in DIC patients without severe renal dysfunction [21]
This study was conducted in patients who had been diagnosed as having DIC according to the Japanese Association for Acute Medicine (JAAM) DIC diagnostic criteria [16, 22]
Summary
Thrombomodulin is a thrombin and protein C receptor on endothelial cell surface and plays an important role in the regulation of coagulation and the innate immune system [1]. Recombinant human soluble thrombomodulin (ART-123, Asahi Kasei Pharma Co., Tokyo, Japan), a novel anticoagulant, was approved in Japan in 2008 for patients with disseminated intravascular coagulation (DIC) [2,3,4]. It has an active extracellular domain, can bind to thrombin, and can activate protein C similar to thrombomodulin [2]. A global Phase 3 study is currently ongoing in patients with severe sepsis and coagulopathy [6]
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