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

 Seuk Keun Choi  ;  Chan Wha Kim  ;  Jong-Tak Kim  ;  Young Seomun  ;  Min Soo Park  ;  Choon Ok Kim 
 CLINICAL DRUG INVESTIGATION , Vol.38(9) : 829-835, 2018 
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Issue Date
Adult ; Batroxobin/administration & dosage* ; Batroxobin/blood* ; Blood Coagulation/drug effects* ; Blood Coagulation/physiology ; Cohort Studies ; Dose-Response Relationship, Drug ; Double-Blind Method ; Healthy Volunteers ; Hemostatics/administration & dosage* ; Hemostatics/blood* ; Humans ; Injections, Intravenous ; Male ; Middle Aged ; Prothrombin Time*/methods ; Recombinant Proteins/administration & dosage ; Thrombin/metabolism ; Young Adult
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, ), number KCT0002518.
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6. Others (기타) > Dept. of Clinical Pharmacology (임상시험센터) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Choon Ok(김춘옥) ORCID logo
Park, Min Soo(박민수) ORCID logo
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