Mechanism Of Action
Corifact (FXIII) is an endogenous plasma glycoprotein
consisting of two A-subunits and two Bsubunits. FXIIIa promotes cross-linking
of fibrin during coagulation and is essential to the physiological protection
of the clot against fibrinolysis. FXIIIa is a transglutaminase enzyme that catalyzes
the cross-linking of the fibrin α- and γ-chains for fibrin stabilization
and renders the fibrin clot more elastic and resistant to fibrinolysis.1,2
FXIIIa also cross-links α2-plasmin inhibitor to the
α-chain of fibrin, resulting in protection of the fibrin clot from
degradation by plasmin. Cross-linked fibrin is the end result of the
coagulation cascade, and provides tensile strength to a primary hemostatic
The B-subunits in plasma have no enzymatic activity, and
function as carrier molecules for the Asubunits. They stabilize the structure of
the A-subunits and protect them from proteolysis.
A 12-week prospective, open-label, multicenter
pharmacokinetic and safety study was conducted in 7 females and 7 males with
congenital FXIII deficiency, ranging in age from 5 to 42 years (3 children, 2 adolescents,
9 adults). One adult male did not complete the pharmacokinetic study.
Each subject received 40 units per kg Corifact
intravenously every 28 days for a total of three doses administered at
approximately 250 units per minute. Blood samples for doses 1 and 2 were drawn
from patients to determine the FXIII activity level at baseline and 30 and 60
minutes after the infusion. Following the infusion of the third dose of
Corifact, blood samples were drawn at regular intervals up to 28 days to
determine the pharmacokinetic parameters. The mean increase in FXIII activity
levels was 83% with a range of 48 to 114% over the baseline after the third
dose. The pharmacokinetic parameters based on baseline adjusted FXIII activity
(Berichrom assay) are shown in Table 3.
Table 3: Pharmacokinetic Parameters (n=13) by
Berichrom Assay Method - Baseline Adjusted Values
|AUC ss, 0-inf (units•hr/mL)
|Css, max (units/mL)
|Css, min (units/mL)
|T max (hr)
|AUC ss, (0-inf)= Area under the plasma concentration
curve from time 0 to infinity at steady state
Css,max : Peak concentration at steady state
Css,min : Trough concentration at steady state
Tmax : Time to peak concentration
Vss : Volume of distribution at steady state
MRT = Mean residence time
SD = Standard deviation
*100% activity corresponds to 1 unit/mL
Animal Toxicology And/Or Pharmacology
Corifact was studied in an acute toxicity study in mice
and rats at doses up to 3550 units per kg and 1420 units per kg, respectively.
Repeat dose toxicity was studied in rats at daily doses up to 350 units per kg for
a period of 14 days. No signs of toxicity were observed in the single dose and
repeat dose studies.
A local tolerance study in rabbits demonstrated no
clinical or histopathological changes at the injection site after intravenous,
intra-arterial or para-venous administration of Corifact.
A thrombogenicity test was performed in rabbits at doses
up to 350 units per kg. Corifact showed no thrombogenic potential at the doses
The postmarketing efficacy and safety trial conducted in
41 subjects who received routine prophylactic treatment (40 U/kg every 28 days
for 52 weeks) for congenital FXIII deficiency, was to verify the clinical
benefit of Corifact by showing correlation between trough levels of FXIII
activity and clinical efficacy. The clinical benefit of Corifact was also
demonstrated by comparing the incidence of bleeding in Corifact-treated
subjects to historical control with congenital FXIII deficiency.
The incidence of spontaneous bleeding episodes requiring
treatment was evaluated. Treatment was defined as an administration of a
FXIII-containing product to treat the bleeding episode. None of the 5 subjects
who experienced a spontaneous bleeding episode (2 nose bleeds, 2 rectal bleeds,
and 1 episode of hematuria associated with a urinary tract infection, and an
indwelling urinary catheter) required treatment with a FXIII-containing
An annualized bleeding rate of 0 episodes per subject per
year for spontaneous bleeding was established when compared to a historical
annualized bleeding rate of 2.5 episodes per subject per year in patients
receiving on-demand treatment of acute bleeding in patients with congenital
Eight bleeding episodes secondary to trauma, and one
associated with surgery were also reported during the 52 weeks of the trial. In
the eight bleeding episodes secondary to trauma, six did not require treatment
with a FXIII-containing product, and two were successfully treated with a
FXIII-containing product (one was treated with Corifact and one with plasma).
The prophylactic administration of Factor XIII
Concentrate (Human) every 28 days in subjects with congenital FXIII deficiency
achieved mean FXIII activity levels between 5% and 20%. FXIII activity was
maintained at ≥5% in ≥97% of subjects and ≥10% in ≥85%
of subjects. Of the 533 doses administered to 41 subjects, dose adjustment was
required on only eight occasions, supporting that 40 U/kg every 28 days is the
appropriate dose for the majority of patients.
Five subjects underwent surgical procedures, four were
elective and one was an emergency. Of the four elective surgeries, three
subjects received Corifact prior to surgery (0 to 7 days prior to surgery) with
no post-operative bleeding. One subject who received Corifact 7 days prior to
surgery experienced bleeding post-extraction of all four wisdom teeth. The bleeding
was stopped four hours after the oral surgery with an additional dose of
Corifact (50% of the subject's routine dose). One subject who required
emergency surgery was pre-treated with plasma.
1. Lauer P, Metzner HJ, Zettlmeissl G, Li M, et al.
Targeted Inactivation of the Mouse Locus Encoding Coagulation Factor XIII-A:
Hemostatic Abnormalities in Mutant Mice and Characterization of the Coagulation
Deficit. Thromb Haemost. 2002;88:967-74.
2. Dardik R, Loscalzo J, Inbal A. Factor XIII (FXIII) and
Angiogenesis. J Thromb Haemost. 2006;4:19- 25.
3. Lusher J, Pipe SW, Alexander S, Nugent D. Prophylactic
therapy with Fibrogammin P is associated with a decreased incidence of bleeding
episodes: a retrospective study. Haemophilia. 2009;1-6.