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

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.

Circulating activated protein C levels are not increased in septic patients treated with recombinant human soluble thrombomodulin

“…3a ). The detected sTM levels were essentially equivalent to those reported in previous clinical studies [ 16 , 17 ] and those adopted in our in vitro assays. Plasma TAT levels were slightly, but significantly, decreased during a 30–60-min period of rTM treatment on day 2 (Fig.…”

“…rTM was administered to patients via drip infusion over a period of 30–60 min. Plasma rTM concentrations peak immediately after the completion of rTM administration [ 16 ]. In our in vitro APC generation assays, APC generation peaked within 10 min and the activity of APC was decreased over time probably because protein C inhibitor, antitrypsin, and α2-macroglobulin bound to and inactivated APC.…”

Thrombomodulin in disseminated intravascular coagulation and other critical conditions—a multi-faceted anticoagulant protein with therapeutic potential

“…The half-life of rTM is approximately 20 h, and more than 50% of the drug is excreted from urine. However, the dose reduction is not necessary even in moderate renal dysfunction [28]. rTM is currently available only in Japan and the cost for 6-day-treatment will be over $3000 in US dollars.…”

Restrictive transfusion strategy for critically injured patients (RESTRIC) trial: a study protocol for a cluster-randomised, crossover non-inferiority trial

“…TRALI is defined according to the Toronto definition, 17 and sepsis is defined according to sepsis-3. 18 Sample size In our previous retrospective multicentre observational study, wherein data were collected from 796 patients with severe trauma from 15 hospitals during a 1-year period, [19][20][21][22][23][24][25][26] 241 patients received RBC concentrates during the first 24 hours after arrival at the ED and 25% of the patients transfused with RBC concentrates died within 28 days after arrival at the ED. Based on these results, we assumed a mortality rate of 25% at 28 days after arrival in the ED among patients receiving a liberal RBC transfusion strategy.…”

“…According to previous studies, this number of patients will allow us to study the outcomes for 2 years. [19][20][21][22][23][24][25][26] Statistical plan All analyses of the primary outcome will be adjusted for clustering within sites. The analysis will use a mixed model with adjustment for intervention, the period as a fixed effect and the sites and the interaction of site with period as a random effect.…”