title: Preclinical safety of recombinant human thrombin.
abstract: Recombinant human thrombin (rhThrombin) is being developed as an alternative to thrombin products purified from pooled human or bovine plasma, which are currently marketed for topical hemostasis. Preclinical studies of rhThrombin were conducted prior to its evaluation as a topical adjunct to surgical hemostasis in clinical trials. No overt clinical pathology or signs were observed in cynomolgus monkeys following implantation of a gelatin sponge containing either rhThrombin or bovine thrombin to a surgical liver wound, and similar gross and microscopic wound healing characteristics were observed over an eight-week recovery period with either compound. Repeated subcutaneous injections of rhThrombin or bovine thrombin to cynomolgus monkeys produced no treatment-related effects. Whereas no monkeys demonstrated anti-rhThrombin antibody seroconversion, specific anti-bovine antibodies were detected in all tested monkeys exposed to bovine thrombin. Addition of rhThrombin or bovine thrombin to mouse fibroblast cells resulted in expected detachment and shape change. Topical application of rhThrombin to rabbits did not cause irritation to the eye, normal skin, or abraded skin. These studies showed that topical, subcutaneous, or implanted rhThrombin was minimally immunogenic, safe, and well tolerated in nonclinical models, and supported the clinical evaluation of rhThrombin in a variety of surgical settings.
authors.affiliation: ZymoGenetics Inc, Seattle, WA 98102, USA.
authors.forename: Jane K
authors.initials: JK
authors.lastname: Heffernan
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Ponce
authors.forename: Linda A
authors.initials: LA
authors.lastname: Zuckerman
authors.forename: John P
authors.initials: JP
authors.lastname: Volpone
authors.forename: Jennifer
authors.initials: J
authors.lastname: Visich
authors.forename: Erika E
authors.initials: EE
authors.lastname: Giste
authors.forename: Nancy
authors.initials: N
authors.lastname: Jenkins
authors.forename: Dan
authors.initials: D
authors.lastname: Boster
authors.forename: Susan
authors.initials: S
authors.lastname: Pederson
authors.forename: Glenn
authors.initials: G
authors.lastname: Knitter
authors.forename: Thomas
authors.initials: T
authors.lastname: Palmer
authors.forename: Margaret
authors.initials: M
authors.lastname: Wills
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Early
authors.forename: Mark C
authors.initials: MC
authors.lastname: Rogge
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005123:Eye / Q000187:drug effects / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006490:Hemostatics / Q000276:immunology / Q000633:toxicity*; D006801:Humans; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D011817:Rabbits; D011994:Recombinant Proteins / Q000276:immunology / Q000633:toxicity*; D023422:Skin Irritancy Tests; D013917:Thrombin / Q000276:immunology / Q000633:toxicity*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D006490:Hemostatics; D011994:Recombinant Proteins; D013917:Thrombin; C513462:recombinant human thrombin