Coagulant Effect and Tolerability of Yeast-Produced Recombinant Batroxobin in Healthy Adult Subjects
Background and Objective
Batroxobin, a snake venom thrombin-like enzyme, converts fibrinogen into fibrin by cleaving fibrinopeptide A. It is used for hemostasis; however, the supply of native batroxobin is limited. Therefore, we developed a recombinant batroxobin (r-batroxobin) from Pichia pastoris and evaluated its pharmacodynamics and safety in humans.
A randomized, double-blind, placebo-controlled, single ascending-dose study was performed. Eight healthy subjects were enrolled in each r-batroxobin dose group (2.5, 5.0, or 10.0 BU/2.0 mL administered intravenously), and randomized to receive r-batroxobin (n = 6) or matching placebo (n = 2). Safety was evaluated during the study, and pharmacodynamics was assessed using prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), and fibrinogen level.
All subjects in each cohort completed the study. No significant changes in PT or aPTT occurred after intravenous r-batroxobin administration. Compared with the placebo group, the fibrinogen level in all r-batroxobin dose groups decreased significantly to 8.68–33.57% from the baseline within 12 h (p ≤ 0.05). The TT in the 5.0 and 10.0 BU/2.0 mL groups significantly increased to 7.53–18.48% from baseline within 12 h compared with that of the placebo group (p ≤ 0.05), whereas that of the 2.5 BU/2.0 mL group exhibited non-significant changes compared with the placebo group. No serious adverse events occurred.
A single intravenous injection of r-batroxobin within a dose range of 2.5–10.0 BU/2.0 mL was well tolerated and resulted in a significant decrease in fibrinogen and prolongation of TT.
This study is registered at the Clinical Research Information Service (CRIS, http://cris.nih.go.kr), number KCT0002518.
We would like to thank the staff at Severance Hospital Clinical Trials Center for their generous cooperation. This randomized clinical trial is registered at the Clinical Research Information Service (CRIS, http://cris.nih.go.kr), number KCT0002518.
Conceptualization: MSP and COK. Conduct of clinical study: COK, MSP, JTK, and YS. Data curation: SKC. Formal analysis: SKC, CWK, and COK; Writing-original manuscript: SKC and COK.
Compliance with Ethical Standards
This study was funded by NC bit Inc., Seongnam, Korea.
Conflict of interest
Jong-Tak Kim and Young Seomun are full-time employees of NC bit Inc, but they did not play a major role in the study design or data analysis. The other authors report no conflicts of interest related to this work.
Institutional Review Board (IRB) of Severance Hospital, Yonsei University College of Medicine (Seoul, Korea) approved the study protocol before the study was conducted (IRB number: 4-2014-0661). All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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