Impact of renal dysfunction on pharmacokinetics of recombinant human thrombomodulin

Impact of renal dysfunction on pharmacokinetics of recombinant human thrombomodulin Kazuhisa Tsuruta, Shinichiro Shirae, M-samer Mouksassi, Kenneth J Gorelick, Inder Kaul Asahi Kasei Pharma America Corporation, USA Pharsight, a Certara Company, Canada Zymo Consulting Group, LLC, USA Background/Purpose: Thrombomodulin α (TMα) is a soluble recombinant human thrombomodulin that has been shown to enhance the reversal of disseminated intravascular coagulation (DIC) and may reduce mortality in subjects with sepsis and DIC. Many sepsis patients have renal impairment, and because TMα is renally cleared, understanding the effects of renal impairment on pharmacokinetics is essential to patient safety. The purpose of this study is to clarify the impact of renal dysfunction on TMα pharmacokinetics (PK). Methods: Population pharmacokinetic (PPK) analysis of TMα was performed using rich samples collected in 24 healthy subjects and sparse samples collected in 368 subjects with sepsis and DIC. In addition, a PK study was conducted in 5 groups of 8 subjects each with different degrees of kidney injury including end-stage renal disease (ESRD) undergoing hemodialysis. Results: PPK analysis indicated that renal function affected the clearance of TMα, but the simulated plasma concentration did not reach the level that is known to increase the bleeding risk (N13000 ng/mL) even in the severe renal impairment group (15 b Ccr ≤ 30 mL/min). Subanalysis by population with severe renal impairment in the global Ph2b study suggested that there were no differences in bleeding events between TMα and placebo (standard of care). Conclusions: The results of the renal PK study indicated that there are no differences in PK between severe impairment and ESRD. Based on the above results, no dose adjustment would be needed for renal impairment including ESRD regardless of their status on hemodialysis.