Background: Despite widespread use of recombinant human soluble thrombomodulin (rTM) for management of coagulopathy in patientswith severe sepsis in Japan, little is known about the pharmacokinetic properties and dosing in the critically ill with coagulopathy during continuous hemodiafiltration (CHDF). rTM is reported to be excreted by kidney, hence the dose for patients with renal impairment is suggested to be reduced to one third of the normal dose. Patients and Methods: We performed a single-center, randomized, prospective study between low-dose (0.02 mg/kg, n=4) and high-dose (0.06 mg/kg, n=4) rTM administration. We evaluated the effect of the high-dose compared with the low-dose on the pharmacokinetics of rTM for the 8 septic disseminated intravascular coagulation (DIC) patients during CHDF. Patients were given rTM during a 30 minute infusion for consecutive 6 days. All patients received CHDF at the time of inclusion. Most of parameters of severity, e.g., APACHE II, DIC score, HMGB1, and interleukin-6, etc., were not different between the two groups. The pharmacokinetic parameters were analyzed by one compartment model. Results: The elimination half-life, clearance, and distribution volume of rTM were similar between the low- and high-dose (29.1 vs 24.1 hr, 1.92 vs 2.83 mL/hr/kg, and 77.1 vs 86.4 mL/kg, respectively), while the peak plasma concentration (Cmax) of rTM, and the AUC of rTM, were approximately 2.7 times higher with the highdose daily infusions compared to the low-dose drip infusions (579 vs 1590 ng/mL and 66300 vs 175100 ng/mL per hr). The time when the concentration of rTM was 9500 ng/mL, i.e., holding time, was significantly longer with the high-dose infusions than with the low-dose (129.0 versus 21.1 hr, p=0.032). Side effects were not observed in all the patients, but one patient in each group deceased because of multiple organ failure. Conclusions: rTM displayed dose-dependent pharmacokinetic behavior with the range of doses used in the clinical setting. As the results, effective blood concentration was achieved under both lowand high-dose administration during CHDF, and also rTM was found not to be bioaccumulative. Therefore, it might be unnecessary to reduce the dose during CHDF even if DIC patients are complicated with renal failure.
Watanabe, E., Yamazaki, S., Setoguchi, D., Sadahiro, T., Tateishi, Y., Suzuki, T., … Oda, S. (2017). Pharmacokinetics of Standard- and Reduced-Dose Recombinant Human Soluble Thrombomodulin in Patients with Septic Disseminated Intravascular Coagulation during Continuous Hemodiafiltration. Frontiers in Medicine, 4. https://doi.org/10.3389/fmed.2017.00015