title: Preclinical safety and pharmacokinetics of recombinant human factor XIII.
abstract: Factor XIII (FXIII) is a thrombin-activated protransglutaminase responsible for fibrin clot stabilization and longevity. Deficiency in FXIII is associated with diffuse bleeding and wound-healing disorders in humans. This report summarizes results from several studies conducted in adult cynomolgus monkeys (M. fascicularis) to evaluate the safety and pharmacokinetics of recombinant human factor XIII A(2) dimer (rFXIII). Intravenous slow bolus injection of rFXIII resulted in the expected formation of the heterotetramer rA(2)cnB(2), prolonged circulating half-life (5-7 days), and increased plasma transglutaminase activity. Recombinant FXIII was well tolerated as a single dose up to 20 mg/kg rFXIII (2840 U/kg), as repeated daily doses up to 6 mg/kg (852 U/kg) for 14 days, and as 3 repeated doses of 8 mg/kg (1136 U/kg) separated by 14 days. Overt toxicity occurred after a single intravenous injection of = 22.5 mg/kg rFXIII (3150 U/kg), or with 2 doses of = 12.5 mg/kg (1775 U/kg) administered within 72 hours. The rFXIII-mediated toxicity was expressed as an acute systemic occlusive coagulopathy. Evaluation of plasma samples from dosed animals demonstrated formation of cross-linked fibrin/fibrinogen oligomers and higher-order protein aggregates, which are hypothesized to be responsible for the observed vessel occlusion and associated embolic sequelae. These results demonstrate that rFXIII-mediated toxicity results from exaggerated pharmacological activity of the molecule at supraphysiological concentrations. The absence of observed toxicological effect with repeated intravenous doses up to 8 mg/kg (1136 U/kg) was used to support an initial clinical dose range of 0.014 to 0.35 mg/kg (2-50 U/kg).
authors.affiliation: ZymoGenetics Inc., 1201 Eastlake Avenue E., Seattle, WA 98102, USA. reap@zgi.com
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Ponce
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Visich
authors.forename: Jane K
authors.initials: JK
authors.lastname: Heffernan
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Lewis
authors.forename: Susan
authors.initials: S
authors.lastname: Pederson
authors.forename: Elen
authors.initials: E
authors.lastname: Lebel
authors.forename: Lydia
authors.initials: L
authors.lastname: Andrews-Jones
authors.forename: Glenn
authors.initials: G
authors.lastname: Elliott
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Palmer
authors.forename: Mark C
authors.initials: MC
authors.lastname: Rogge
mesh_terms: D000818:Animals; D001778:Blood Coagulation Disorders / Q000139:chemically induced* / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005176:Factor XIII / Q000493:pharmacokinetics* / Q000633:toxicity*; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D009206:Myocardium / Q000473:pathology; D011994:Recombinant Proteins; D013927:Thrombosis / Q000139:chemically induced / Q000473:pathology; D011503:Transglutaminases / Q000097:blood
chemical_list: D011994:Recombinant Proteins; D005176:Factor XIII; D011503:Transglutaminases