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Thromb Haemost 2017; 117(05): 851-859
DOI: 10.1160/TH16-07-0547
Coagulation and Fibrinolysis
Schattauer GmbH

Pharmacokinetics of recombinant human soluble thrombomodulin in disseminated intravascular coagulation patients with acute renal dysfunction

Mineji Hayakawa
1   Emergency and Critical Care Center, Hokkaido University Hospital, Hokkaido, Japan
,
Shigeki Kushimoto
2   Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, Tohoku, Japan
,
Eizo Watanabe
3   Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
,
Koji Goto
4   Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine, Oita University, Oita, Japan
,
Yasushi Suzuki
5   Department of Critical Care Medicine, Iwate Medical University, Iwate, Japan
,
Toru Kotani
6   Department of Anesthesiology and Intensive Care Medicine, Tokyo Women’s Medical University, Tokyo, Japan
,
Takeyuki Kiguchi
7   Department of Emergency and Critical Care, Osaka General Medical Center, Osaka Japan
,
Tomoaki Yatabe
8   Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kochi, Japan
,
Jun Tagawa
9   Clinical Development Center, Asahi Kasei Pharma Co., Tokyo, Japan
,
Fumiyo Komatsu
9   Clinical Development Center, Asahi Kasei Pharma Co., Tokyo, Japan
,
Satoshi Gando
1   Emergency and Critical Care Center, Hokkaido University Hospital, Hokkaido, Japan
› Author Affiliations Financial support: Financial support for this study was provided by Asahi Kasei Pharma Co., Tokyo, Japan.
Further Information

Publication History

Received: 20 July 2017

Accepted after major revision: 25 January 2017

Publication Date:
28 November 2017 (online)

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Summary

Recombinant 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.

Keywords

Plasma concentration - disseminated intravascular coagulation - pharmacokinetics - renal dysfunction - sepsis
 

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