title: Pharmacokinetics of Standard- and Reduced-Dose Recombinant Human Soluble Thrombomodulin in Patients with Septic Disseminated Intravascular Coagulation during Continuous Hemodiafiltration.
abstract: BACKGROUND
  Recombinant human soluble thrombomodulin (rTM) is reportedly excreted by the kidneys; therefore, the recommended dose for patients with renal impairment is one-third of the standard dose. The aim of this study was to evaluate whether this reduced dose of rTM achieves effective drug concentrations that are comparable to those of the standard dose in treating sepsis-induced disseminated intravascular coagulation (DIC) during continuous hemodiafiltration (CHDF).
  
  
  METHODS
  Eight patients in an intensive care unit were randomized to receive either reduced-dose (0.02 mg/kg,n= 4) or standard-dose (0.06 mg/kg,n= 4) rTM. We evaluated the effect of standard dose in comparison to that of reduced dose on the pharmacokinetics (PKs) of rTM for the sepsis-induced DIC patients receiving CHDF. Patients received rTM during a 30-min infusion for six consecutive days. PK parameters of rTM were analyzed using the one-compartment model.
  
  
  RESULTS
  The elimination half-life, clearance (T1/2), and distribution volume of sTM were similar between the reduced and standard doses. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) of sTM were approximately 2.5 times higher with standard-dose daily infusions than that with reduced-dose drip infusions (p= 0.041 and 0.062, respectively). The time when the blood concentration of sTM was >500 ng/mL, i.e., the holding time, was significantly longer with standard-dose infusions than those with reduced dose (p= 0.039).
  
  
  CONCLUSIONS
  rTM displayed dose-dependent PK behavior at clinically relevant doses. During CHDF, effective blood concentration of rTM was not achieved with the reduced dose, and rTM was found to not bioaccumulate. Therefore, this pilot study suggests that reducing the rTM dose is unnecessary, even in sepsis-induced DIC patients who require CHDF. However, we need to perform a definitive study to determine the dosage of rTM for the case.
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University , Chiba City , Japan.
authors.forename: Eizo
authors.initials: E
authors.lastname: Watanabe
authors.affiliation: Division of Pharmacy, Chiba University Hospital , Chiba City , Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University , Chiba City , Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Setoguchi
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University , Chiba City , Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Sadahiro
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University , Chiba City , Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tateishi
authors.affiliation: Division of Pharmacy, Chiba University Hospital , Chiba City , Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Division of Pharmacy, Chiba University Hospital , Chiba City , Japan.
authors.forename: Itsuko
authors.initials: I
authors.lastname: Ishii
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University , Chiba City , Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Oda
keywords: acute kidney injury; coagulopathy; renal dysfunction; renal replacement therapy; sepsis