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Preclinical Safety and Pharmacokinetics of Recombinant Human Factor XIII
1 ZymoGenetics, Inc., Seattle, Washington 98102, USA Correspondence: Address correspondence to: Dr. Rafael Ponce, ZymoGenetics, Inc., 1201 Eastlake Ave. E., Seattle, WA 98102, USA; e-mail:reap{at}zgi.com
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 A2 dimer (rFXIII). Intravenous slow bolus injection of rFXIII resulted in the expected formation of the heterotetramer rA2cnB2, 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
Key Words: Factor XIII • Recombinant Factor XIII • preclinical safety • cynomolgus monkey • pharmacokinetics • coagulation factor Abbreviations: rFXIII, rA2, recombinant human FXIII [A2] dimer • FXIII, pFXIII, A2B2, plasma FXIII [A2B2] heterotetramer • cFXIII, cellular, placental, or platelet FXIII [A2]dimer • A2, factor XIII A-dimer • rA2cnB2, de-lineates the complex formed when mixing rFXIII and cynomolgus FXIII-B subunit • FXIIIa, all or any forms of active FXIII • FXIIIa*, proteolytically activated FXIII • FXIIIa°, nonproteolytically activated FXIII • ZGI, ZymoGenetics, Inc. (Seattle, WA) • SA-HRP, streptavidin-horseradish per-oxidase • NHS-LC biotin, succinimidyl-6-(biotinamido) hexanoate • OPD, (ortho-phenylenediamine dihydrochloride) • TMB, 3,3'5,5' tetramethylbenzidine
Toxicologic Pathology, Vol. 33, No. 4,
495-506 (2005) This article has been cited by other articles:
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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). 
