Analysis of fibrinogen concentrate pharmacokinetics and dosing for bleeds and surgery in adults, adolescents, and children with congenital afibrinogenaemia and hypofibrinogenaemia.

Abstract

Congenital afibrinogenaemia and hypofibrinogenaemia are rare coagulation disorders where clotting is impaired due to a lack of fibrinogen. Consequent bleeding episodes (BEs) are treated using human fibrinogen concentrate (HFC). This post-hoc analysis compared HFC pharmacokinetics (PK) and dosing between patient age groups and defined the in vivo recovery (IVR) for children with a- and hypofibrinogenaemia. The analysis used data from the FORMA-01 (Phase 2), FORMA-02 and FORMA-04 (Phase 3) multinational, prospective, open-label studies in patients with a- and hypofibrinogenaemia. HFC PK in adults/adolescents (≥12 years; FORMA-01) and children (<12 years; FORMA-04) was examined. Haemostatic efficacy in BE treatment and perioperative prophylaxis was examined in FORMA-02 and FORMA-04 using an objective 4-point scale, with success defined as excellent/good. Median (range) age was 23 years for FORMA-01 (12-53; n=22), 26.5 years for FORMA-02 (12-54; n=25), and 6 years for FORMA-04 (1-10; n=13). Mean PK parameters were lower for children (AUC, Cmax , IVR; p=.02), while clearance was higher. Median (range) total dose of HFC for all BEs was 59.41mg/kg (32.12-273.80) in adults/adolescents and was 24% higher (ns) in children at 73.91mg/kg (47.45-262.50). Treatment was successful in 98.9% of the 89 BEs in adults/adolescents and in 100% of the 10 BEs in children, with comparable results for perioperative prophylaxis. As expected, HFC PK differed between adults/adolescents and children. However, with the higher doses given to children, HFC showed similar efficacy across age groups. Dose adaptation based on age groups appears recommendable.