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

Summary

Recombinant 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.

Keywords

Plasma concentration - disseminated intravascular coagulation - pharmacokinetics - renal dysfunction - sepsis

 

Conflicts of interest

M. Hayakawa received a research funding for another basic research project and lecturer’s fee from Asahi Kasei Pharma Co. S. Kushimoto received consultancy funding and lecturer’s fee from Asahi Kasei Pharma Co. E. Watanabe received a research funding from Asahi Kasei Pharma Co. for another collaborative study. S. Gando received consultancy funding from Asahi Kasei Pharma Co. J. Tagawa and F. Komatsu are employees of Asahi Kasei Pharma Co. The other authors declare that they have no competing interests.

• References

• 1 Weiler H. Regulation of inflammation by the protein C system. Crit Care Med 2010; 38: S18-25.
• 2 Saito H, Maruyama I, Shimazaki S. et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007; 05: 31-41.
• 3 Wada H, Japanese Society of Thrombosis Hemostasis DICs. Okamoto K. et al. Addition of recommendations for the use of recombinant human thrombomodulin to the Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res 2014; 134: 924-925.
• 4 Iba T, Gando S, Thachil J. Anticoagulant therapy for sepsis-associated disseminated intravascular coagulation: the view from Japan. J Thromb Haemost 2014; 12: 1010-1019.
• 5 Vincent JL, Ramesh MK, Ernest D. et al. A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Care Med 2013; 41: 2069-2079.
• 6 Phase 3 safety and efficacy study of ART-123 in subjects with severe sepsis and coagulopathy. https://clinicaltrials.gov/ct2/show/NCT01598831?term=art-123&rank=4 Accessed July 1, 2017
• 7 Esmon CT, Esmon NL, Harris KW. Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation. J Biol Chem 1982; 257: 7944-7947.
• 8 Stearns-Kurosawa DJ, Kurosawa S, Mollica JS. et al. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA 1996; 93: 10212-10216.
• 9 Yamakawa K, Fujimi S, Mohri T. et al. Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study. Crit Care 2011; 15: R123.
• 10 Yamakawa K, Ogura H, Fujimi S. et al. Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. Intensive Care Med 2013; 39: 644-652.
• 11 Takazono T, Nakamura S, Imamura Y. et al. A retrospective comparative study of recombinant human thrombomodulin and gabexate mesilate in sepsis-induced disseminated intravascular coagulation patients. J Infect Chemother 2014; 20: 484-488.
• 12 Hayakawa M, Yamakawa K, Saito S. et al. Recombinant human soluble thrombomodulin and mortality in sepsis-induced disseminated intravascular coagulation. A multicentre retrospective study. Thromb Haemost 2016; 115: 1157-1166.
• 13 Tagami T, Matsui H, Fushimi K. et al. Use of recombinant human soluble thrombomodulin in patients with sepsis-induced disseminated intravascular coagulation after intestinal perforation. Front Med 2015; 02: 7.
• 14 Tagami T, Matsui H, Horiguchi H. et al. Recombinant human soluble thrombomodulin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J Thromb Haemost 2015; 13: 31-40.
• 15 Rangel-Frausto MS, Pittet D, Costigan M. et al. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. J Am Med Assoc 1995; 273: 117-123.
• 16 Gando S, Saitoh D, Ogura H. et al. Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: results of a multicenter, prospective survey. Crit Care Med 2008; 36: 145-150.
• 17 Seki Y, Wada H, Kawasugi K. et al. A prospective analysis of disseminated intravascular coagulation in patients with infections. Intern Med 2013; 52: 1893-1898.
• 18 Gando S, Saitoh D, Ogura H. et al. A multicenter, prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis. Crit Care 2013; 17: R111.
• 19 Nakashima M, Uematsu T, Umemura K. et al. A novel recombinant soluble human thrombomodulin, ART-123, activates the protein C pathway in healthy male volunteers. J Clin Pharmacol 1998; 38: 540-544.
• 20 Nakashima M, Kanamaru M, Umemura K. et al. Pharmacokinetics and safety of a novel recombinant soluble human thrombomodulin, ART-123, in healthy male volunteers. J Clin Pharmacol 1998; 38: 40-44.
• 21 Hayakawa M, Yamamoto H, Honma T. et al. Pharmacokinetics and pharmacodynamics of recombinant soluble thrombomodulin in disseminated intravascular coagulation patients with renal impairment. Shock 2012; 37: 569-573.
• 22 Gando S, Iba T, Eguchi Y. et al. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med 2006; 34: 625-631.
• 23 Tsuruta K, Kodama T, Serada M. et al. Pharmacokinetics of recombinant human soluble thrombomodulin, thrombomodulin alfa in the rat. Xenobiotica 2009; 39: 125-134.
• 24 Tsuruta K, Yamada Y, Serada M. et al. Model-based analysis of covariate effects on population pharmacokinetics of thrombomodulin alfa in patients with disseminated intravascular coagulation and normal subjects. J Clin Pharmacol 2011; 51: 1276-1285.
• 25 Mouksassi M, Marier J, Bax L. et al. Population pharmacokinetic analysis of thrombomodulin alfa to support dosing rationale in patients with renal impairment. Clin Pharmacol Drug Dev 2015; 04: 210-217.
• 26 Boehme MW, Galle P, Stremmel W. Kinetics of thrombomodulin release and endothelial cell injury by neutrophil-derived proteases and oxygen radicals. Immunology 2002; 107: 340-349.
• 27 Gando S, Kameue T, Matsuda N. et al. Serial changes in neutrophil-endothelial activation markers during the course of sepsis associated with disseminated intravascular coagulation. Thromb Res 2005; 116: 91-100.
• 28 Linehan SA, Martinez-Pomares L, Gordon S. Mannose receptor and scavenger receptor: two macrophage pattern recognition receptors with diverse functions in tissue homeostasis and host defense. Adv Exp Med Biol 2000; 479: 1-14.
• 29 Terpstra V, van Amersfoort ES, van Velzen AG. et al. Hepatic and extrahepatic scavenger receptors: function in relation to disease. Arterioscler Thromb Vasc Biol 2000; 20: 1860-1872.
• 30 Hayakawa M, Ito Y, Fujita I. et al. Pharmacokinetics and the most suitable regimen of panipenem/beta mipron in critically ill patients receiving continuous renal replacement therapy: a pilot study. ASAIO J 2006; 52: 398-403.
• 31 Hayakawa M, Fujita I, Iseki K. et al. The administration of ciprofloxacin during continuous renal replacement therapy: pilot study. ASAIO J 2009; 55: 243-245.
• 32 Mohri M. ART-123: Recombinant human soluble thrombomodulin. Cardiovasc Drug Rev 2000; 18: 312-325.
• 33 Mohri M, Sugimoto E, Sata M. et al. The inhibitory effect of recombinant human soluble thrombomodulin on initiation and extension of coagulation--a comparison with other anticoagulants. Thromb Haemost 1999; 82: 1687-1693.
• 34 Carlier M, Dumoulin A, Janssen A. et al. Comparison of different equations to assess glomerular filtration in critically ill patients. Intensive Care Med 2015; 41: 427-435.