Pharmacokinetics of Standard- and Reduced-Dose Recombinant Human Soluble Thrombomodulin in Patients with Septic Disseminated Intravascular Coagulation during Continuous Hemodiafiltration.

Eizo Watanabe,Itsuko Ishii,Daisuke Setoguchi,Yoshihisa Tateishi,Tatsuya Suzuki,Tomohito Sadahiro,Shingo Yamazaki,Shigeto Oda

doi:10.3389/fmed.2017.00015

Eizo Watanabe, Itsuko Ishii + Show 6 more

Open Access

https://doi.org/10.3389/fmed.2017.00015

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Abstract

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). 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. 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). 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.

Highlights

Severe sepsis continues to be life threatening and the most common cause of death in intensive care units (ICUs) (1)
The plasma rTM and soluble TM concentrations were determined with enzyme-linked immunosorbent assay (ELISA), using two different mouse monoclonal antibodies against thrombomodulin (14)
The number of patients included in the present study was less, no evaluated outcomes were different between the reduced- and standard-dose groups (Table 1)

Summary

Introduction

Severe sepsis continues to be life threatening and the most common cause of death in intensive care units (ICUs) (1). In the pathophysiology of severe sepsis, disseminated intravascular coagulation (DIC) has been recently recognized to play a key role and to be a therapeutic target. Antithrombin-III (ATIII) and tissue factor pathway inhibitor had no effect on mortality in clinical trials (2, 3). One of the anticoagulation factors, activated protein C (APC), was promoted as an antiseptic agent (i.e., XigrisTM) but was later withdrawn owing to the negative results in the PROWESS SHOCK trial (4). RTM promotes protein C activation by thrombin, resulting in the formation of APC. Thereafter, APC inhibits thrombin generation by inactivating coagulation factors Va and VIIIa to interrupt activation of blood coagulation (6). APC has anti-inflammatory properties, interfering especially with the activation of complement and the inactivation of high mobility group box 1 (HMGB1), a late phase death mediator in severe sepsis (7)

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