Skip to main content
SpringerLink
Log in

Coagulant Effect and Tolerability of Yeast-Produced Recombinant Batroxobin in Healthy Adult Subjects

  • Original Research Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

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.

Methods

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.

Results

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.

Conclusions

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.

Registration

This study is registered at the Clinical Research Information Service (CRIS, http://cris.nih.go.kr), number KCT0002518.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Kauvar DS, Wade CE. The epidemiology and modern management of traumatic hemorrhage: US and international perspectives. Crit Care. 2005;9(Suppl 5):S1–9.

    Article  Google Scholar 

  2. Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care. 2016;20:100.

  3. Davenport R, Khan S. Management of major trauma haemorrhage: treatment priorities and controversies. Br J Haematol. 2011;155(5):537–48.

    Article  CAS  Google Scholar 

  4. Douketis JD, Berger PB, Dunn AS, Jaffer AK, Spyropoulos AC, Becker RC, et al. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):299S–339S.

  5. Seghatchian J, Samama MM. Massive transfusion: an overview of the main characteristics and potential risks associated with substances used for correction of a coagulopathy. Transf Apher Sci. 2012;47(2):235–43.

    Article  Google Scholar 

  6. Sihler KC, Napolitano LM. Complications of massive transfusion. Chest. 2010;137(1):209–20.

    Article  Google Scholar 

  7. Schulman S. Pharmacologic tools to reduce bleeding in surgery. Hematol Am Soc Hematol Educ Program. 2012;2012:517–21.

    Google Scholar 

  8. Kumar VA, Wickremasinghe NC, Shi S, Hartgerink JD. Nanofibrous snake venom hemostat. ACS Biomater Sci Eng. 2015;1(12):1300–5.

    Article  CAS  Google Scholar 

  9. Seon GM, Lee MH, Kwon BJ, Kim MS, Koo MA, Kim D, et al. Functional improvement of hemostatic dressing by addition of recombinant batroxobin. Acta Biomater. 2017;48:175–85.

    Article  CAS  Google Scholar 

  10. Hu H, Chen L, Frary CE, Chang C, Hui H, Zhang H, et al. The beneficial effect of Batroxobin on blood loss reduction in spinal fusion surgery: a prospective, randomized, double-blind, placebo-controlled study. Arch Orthop Trauma Surg. 2015;135(4):491–7.

    Article  Google Scholar 

  11. Aronson DL. Comparison of the actions of thrombin and the thrombin-like venom enzymes ancrod and batroxobin. Thromb Haemost. 1976;36(1):9–13.

    Article  CAS  Google Scholar 

  12. You W, Choi W, Koh Y, Shin H, Jang Y, Chung K. Functional characterization of recombinant batroxobin, a snake venom thrombin-like enzyme, expressed from Pichia pastoris. FEBS Lett. 2004;571(1–3):67–73.

    Article  CAS  Google Scholar 

  13. Lochnit G, Geyer R. Carbohydrate structure analysis of batroxobin, a thrombin-like serine protease from Bothrops moojeni venom. Eur J Biochem. 1995;228(3):805–16.

    Article  CAS  Google Scholar 

  14. Jayandharan G, Nair S, Poonnoose P, Thomas R, John J, Keshav S, et al. Polymorphism in factor VII gene modifies phenotype of severe haemophilia. Haemophilia. 2009;15(6):1228–36.

    Article  CAS  Google Scholar 

  15. Key NS, Makris M, Lillicrap D. Practical hemostasis and thrombosis. 3rd ed. Chichester, West Sussex: Wiley; 2017.

  16. Hughes-Jones NC, Wickramasinghe SN, Hatton C. Lecture notes haematology. Chichester: Wiley; 2008.

  17. Tanaka KA, Key NS, Levy JH. Blood coagulation: hemostasis and thrombin regulation. Anesth Analg. 2009;108(5):1433–46.

    Article  CAS  Google Scholar 

  18. Xu C, Wu A, Yue Y. Which is more effective in adolescent idiopathic scoliosis surgery: batroxobin, tranexamic acid or a combination? Arch Orthop Trauma Surg. 2012;132(1):25–31.

    Article  Google Scholar 

  19. Liu KA, Dipietro Mager NA. Women’s involvement in clinical trials: historical perspective and future implications. Pharm Pract (Granada). 2016;14(1):1–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Biotechnology, Korea University, Seoul, South Korea

    Seuk Keun Choi & Chan Wha Kim

  2. R&D Center, NC bit Inc., Seongnam, South Korea

    Jong-Tak Kim & Young Seomun

  3. Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea

    Min Soo Park & Choon Ok Kim

  4. Department of Pediatrics, Yonsei University College of Medicine, Seoul, South Korea

    Min Soo Park

Authors
  1. Seuk Keun Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chan Wha Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jong-Tak Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Young Seomun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Min Soo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Choon Ok Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Choon Ok Kim.

Ethics declarations

Funding

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.

Ethical approval

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

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Choi, S.K., Kim, C.W., Kim, JT. et al. Coagulant Effect and Tolerability of Yeast-Produced Recombinant Batroxobin in Healthy Adult Subjects. Clin Drug Investig 38, 829–835 (2018). https://doi.org/10.1007/s40261-018-0673-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-018-0673-x

Search

Navigation