title: Analysis of the safety and pharmacodynamics of human fibrinogen concentrate in animals.
abstract: Fibrinogen, a soluble 340kDa plasma glycoprotein, is critical in achieving and maintaining hemostasis. Reduced fibrinogen levels are associated with an increased risk of bleeding and recent research has investigated the efficacy of fibrinogen concentrate for controlling perioperative bleeding. European guidelines on the management of perioperative bleeding recommend the use of fibrinogen concentrate if significant bleeding is accompanied by plasma fibrinogen levels less than 1.5-2.0g/l. Plasma-derived human fibrinogen concentrate has been available for therapeutic use since 1956. The overall aim of the comprehensive series of non-clinical investigations presented was to evaluate i) the pharmacodynamic and pharmacokinetic characteristics and ii) the safety and tolerability profile of human fibrinogen concentrate Haemocomplettan P® (RiaSTAP®). Pharmacodynamic characteristics were assessed in rabbits, pharmacokinetic parameters were determined in rabbits and rats and a safety pharmacology study was performed in beagle dogs. Additional toxicology tests included: single-dose toxicity tests in mice and rats; local tolerance tests in rabbits; and neoantigenicity tests in rabbits and guinea pigs following the introduction of pasteurization in the manufacturing process. Human fibrinogen concentrate was shown to be pharmacodynamically active in rabbits and dogs and well tolerated, with no adverse events and no influence on circulation, respiration or hematological parameters in rabbits, mice, rats and dogs. In these non-clinical investigations, human fibrinogen concentrate showed a good safety profile. This data adds to the safety information available to date, strengthening the current body of knowledge regarding this hemostatic agent.
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, Marburg, Germany. Electronic address: andrea.beyerle@cslbehring.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Beyerle
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, Marburg, Germany.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Nolte
authors.affiliation: CSL Behring GmbH, Medical Affairs, Marburg, Germany; Department of Anaesthesiology, Perioperative Medicine and General Intensive Care, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Cristina
authors.initials: C
authors.lastname: Solomon
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, Marburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Herzog
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, Marburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dickneite
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005340:Fibrinogen / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity*; D006168:Guinea Pigs; D006487:Hemostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
chemical_list: D005340:Fibrinogen
keywords: Efficacy; Fibrinogen concentrate; Pharmacokinetics; Safety; Thromboelastometry