Pharmacokinetics and safety of fibrinogen concentrate.
BACKGROUND
Although fibrinogen concentrate has been available for the treatment of congenital fibrinogen deficiency for years, knowledge of its pharmacokinetics comes from only two small studies.


OBJECTIVE
To assess the pharmacokinetic (PK) profile, clot integrity and safety of fibrinogen concentrate (human) (FCH) in patients with afibrinogenemia.


METHODS
A multinational, prospective, open-label, uncontrolled study of patients with afibrinogenemia > or = 6 years of age was conducted in the USA and Italy. Plasma was collected before and after infusion for PK analyses and evaluation by rotational thromboelastometry of maximum clot firmness (MCF) to assess clot integrity. Safety was assessed on the basis of adverse events and laboratory parameters.


RESULTS
After a single dose of 70 mg kg(-1) body weight (b.w.) FCH in 14 patients, median incremental in vivo recovery was a 1.7 mg dL(-1) increase per mg kg(-1) b.w., and median levels were 1.3 g L(-1) for fibrinogen activity and antigen 1 h after infusion. Median half-life (t(1/2)) was 77.1 h for fibrinogen activity and 88.0 h for antigen. Plasma recovery in children < 16 years old was similar to that in adults aged 16 to < 65 years, but the t(1/2) and area under the curve were decreased, with an increased steady-state volume and clearance. MCF increased by a mean of 8.9 mm from baseline to 1 h after infusion of FCH (P < 0.0001). All four adverse events reported were mild, and none was serious or related to study drug.


CONCLUSIONS
These PK findings confirm a rapid increase in plasma fibrinogen levels after infusion with FCH. Together with the clot integrity and safety data and published data on efficacy, the results support the idea that FCH substitution can restore hemostasis with a good safety profile.
Manco-Johnson
M J
MJ
Mountain States Regional Hemophilia & Thrombosis Center, Department of Pediatrics, University of Colorado Denver, Aurora, CO 80010, USA. Marilyn.Manco-Johnson@ucdenver.edu
Dimichele
D
D
Castaman
G
G
Fremann
S
S
Knaub
S
S
Kalina
U
U
Peyvandi
F
F
Piseddu
G
G
Mannucci
P
P
D000293:Adolescent; D000328:Adult; D000347:Afibrinogenemia / Q000188:drug therapy*; D000367:Age Factors; D001780:Blood Coagulation Tests; D002648:Child; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005340:Fibrinogen / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D010599:Pharmacokinetics; D013916:Thrombelastography; D014481:United States; D055815:Young Adult
D005340:Fibrinogen