Nonclinical analysis of the safety, pharmacodynamics, and pharmacokinetics of plasma-derived human FXIII concentrate in animals.

Abstract

Factor XIII (FXIII) is a coagulation protein which plays a major role in hemostasis by covalently cross‐linking fibrin molecules, thereby stabilizing the blood clot and increasing resistance to fibrinolysis. FXIII deficiency, either congenital or acquired, is associated with spontaneous bleeding, increased bleeding time, and poor wound healing. Purified plasma‐derived human FXIII concentrate (pd hFXIII) has been available since 1993 for therapeutic use in congenital FXIII deficiency. This set of nonclinical investigations aimed to evaluate the pharmacodynamic effects and assess the safety profile of pd hFXIII. The efficacy and safety of pd hFXIII were evaluated by pharmacodynamic, pharmacokinetic, and toxicity studies in mice and rats, safety pharmacology studies in dogs, neoantigenicity study, local tolerance, and thrombogenicity tests in rabbits. Administration of pd hFXIII resulted in the correction of deficits in clot formation kinetics and strength as measured by thromboelastometry, and was not associated with thrombus formation up to 350 IU/kg in FXIII knockout mice. There was no production of neoantigens resulting from the viral elimination manufacturing steps detected, and no adverse reactions were observed in toxicity studies with single doses up to 3550 IU/kg in mice and 1420 IU/kg in rats; nor from repeat doses of 350 IU/kg in rats. In addition, local tolerance tests revealed a good tolerability profile in rabbits. Overall, this data showed that pd hFXIII was well tolerated and pharmacodynamically active in preclinical animal models, supporting pd hFXIII as a therapy for FXIII deficiency.