Pharmacokinetic Evaluation of a Fibrinogen Concentrate in Patients with Congenital Fibrinogen Deficiency.

BACKGROUND: Congenital fibrinogen deficiency is a rare bleeding disorder and comprises fibrinogen abnormalities that result in either reductions in the quantity (hypofibrinogenemia and afibrinogenemia) or structure and functionality (dysfibrinogenemia) of fibrinogen. The pharmacokinetics (PK) and surrogate efficacy of a plasma-derived fibrinogen concentrate was studied in a prospective, open, non-controlled, multinational clinical study in patients with confirmed afibrinogenemia.

METHODS: Patients had to have < 0.20 g/L plasma fibrinogen activity, be in a non-bleeding state and receive a single dose of 70 mg/kg body weight. Maximum clot firmness (MCF), determined via validated thrombelastography (TEG), was used as a surrogate endpoint for hemostatic efficacy. Standard PK parameters were analyzed in a central laboratory with a validated Clauss assay and an ELISA.

RESULTS: A total of 15 patients were treated at 10 centers in the US and Italy. Of these, 5 (33.3%) were female. The mean age was 30 years, with 11 subjects (73.3%) in the age group of 16 to <65 years and the remaining between 8 and 14 years.

PK RESULTS: Both median fibrinogen plasma antigen and activity levels reached a maximum within 30 minutes to 1 h post-infusion and decreased continuously afterwards. Median fibrinogen plasma activity levels were at or close to the limit of detection by Day 10 post-infusion. PK findings were similar for fibrinogen activity and antigen. Median Cmax and AUC were 1.3 g/L and 126.8 hours*mg/mL, with a median t1/2 of 77.1 hours for fibrinogen activity. For fibrinogen antigen, median Cmax and AUC were 1.3 g/L and 122.4 hours*mg/mL, with a median t1/2 of 88.0 hours. Whereas no statistically relevant effect of gender was seen on the PK parameters for fibrinogen activity, subjects <16 years old (N=4) had higher median Vss, and Cl values and lower median t1/2, AUC, and MRT values than older subjects (N=10). The median incremental IVR was 1.7 mg/dL increase per mg/kg body weight. for fibrinogen activity and antigen.

EFFICACY: The mean change in MCF between pre-infusion and 1 hour post-infusion was (8.9 mm) (p<0.0001). A secondary analysis performed as a sensitivity analysis in the ITT population confirmed this result (mean change of 10.3 mm; p<0.0001). Mean change from pre-infusion to 1 hour post-infusion was similar for subjects <16 years of age (9.9 mm; N=4) and subjects ≥16 to <65 years of age (8.5 mm; N=10) as well as for males (9.0 mm; N=9) and females (8.8 mm; N=5).

SAFETY: Four adverse events from two patients were reported. All were mild, non-serious and assessed by the investigators as not related to study medication.

CONCLUSION: The PK results for this study of a plasma-derived fibrinogen concentrate showed a sufficient and rapid increase in fibrinogen plasma level and a long half-life. The study demonstrated a significant increase in MCF as a surrogate efficacy parameter and a good safety profile for fibrinogen concentrate in patients with afibrinogenemia.