Safety and pharmacokinetics of recombinant factor XIII-A2 administration in patients with congenital factor XIII deficiency.
Congenital factor XIII (FXIII) deficiency is associated with a tendency for severe bleeding, a risk for spontaneous abortion, and a high rate of spontaneous intracranial hemorrhage. This phase 1 escalating-dose study was developed to evaluate the safety and pharmacokinetics of a single administration of human recombinant FXIII-A2 (rFXIII-A2) homodimer in adults with congenital FXIII deficiency. Pharmacokinetics and activity of rXIII and changes in endogenous B subunit levels were assessed. Recombinant FXIII-A2 homodimer were complexed with endogenous FXIII-B subunits to form an FXIII-A2B2 heterotetramer with a half-life of 8.5 days, similar to that of endogenous FXIII. The median dose response was a 2.4% increase in FXIII activity based on unit per kilogram rFXIII administered. After the administration of rFXIII-A2, clot solubility normalized as measured by clot lysis in urea. Clot strength and resistance to fibrinolysis, as assessed by thromboelastography, also improved. Safety reviews were conducted before each dose escalation; no serious adverse events, including bleeding or thrombosis, were noted during the study. In addition, there was no evidence of the generation of specific antibodies to rFXIII or yeast proteins. Recombinant FXIII appears to be a safe and potentially effective alternative for FXIII replacement in patients with FXIII deficiency.
Department of Hematology, Children's Hospital of Orange County, Orange, CA 92868, USA.
Amy E
AE
Lovejoy
Tom C
TC
Reynolds
Jennifer E
JE
Visich
Michael D
MD
Butine
Guy
G
Young
Melissa A
MA
Belvedere
Rachelle C
RC
Blain
Susan M
SM
Pederson
Laura M
LM
Ishak
Diane J
DJ
Nugent
D000328:Adult; D000368:Aged; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005176:Factor XIII / Q000032:analysis; D005177:Factor XIII Deficiency / Q000151:congenital / Q000188:drug therapy* / Q000276:immunology; D026122:Factor XIIIa / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012995:Solubility; D013916:Thrombelastography; D013997:Time Factors
D011994:Recombinant Proteins; C521905:recombinant factor XIII-A2; D005176:Factor XIII; C054380:factor XIIIb; D026122:Factor XIIIa