title: Pharmacokinetics of recombinant human soluble thrombomodulin in disseminated intravascular coagulation patients with acute renal dysfunction.
abstract: 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.
authors.affiliation: Mineji Hayakawa, MD, PhD, Emergency and Critical Care Center, Hokkaido University Hospital, N14W5 Kita-ku, Sapporo 060-8648 Japan, Tel.: +81 11 706 7377, Fax: +81 11 706 7378, E-mail: mineji@dream.com.
authors.forename: Mineji
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kushimoto
authors.forename: Eizo
authors.initials: E
authors.lastname: Watanabe
authors.forename: Koji
authors.initials: K
authors.lastname: Goto
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Toru
authors.initials: T
authors.lastname: Kotani
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Kiguchi
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Yatabe
authors.forename: Jun
authors.initials: J
authors.lastname: Tagawa
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Komatsu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Gando
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D006207:Half-Life; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007564:Japan; D007668:Kidney / Q000503:physiopathology*; D007674:Kidney Diseases / Q000150:complications / Q000175:diagnosis / Q000503:physiopathology*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D065667:Renal Elimination; D012720:Severity of Illness Index; D018180:Thrombomodulin / Q000008:administration & dosage / Q000097:blood; D016896:Treatment Outcome
chemical_list: C472045:ART123; D000925:Anticoagulants; D011994:Recombinant Proteins; D018180:Thrombomodulin
keywords: Plasma concentration; disseminated intravascular coagulation; pharmacokinetics; renal dysfunction; sepsis