Population pharmacokinetics of a triple-secured fibrinogen concentrate administered to afibrinogenaemic patients: Observed age- and body weight-related differences and consequences for dose adjustment in children.

AIMS: The pharmacokinetics (PK) of a triple-secured fibrinogen concentrate (FC) was assessed in patients ≥40 kg by noncompartmental analysis over a period of 14 days with multiple blood samples. Limited PK time point assessments in children lead to consideration of using Bayesian estimation for paediatric data. The objectives were (i) to define the population PK of FC in patients with afibrinogenaemia; (ii) to detect age- and body weight-related differences and consequences for dose adjustment. METHODS: A population PK model was built using plasma fibrinogen activity data collected in 31 patients aged 1 to 48 years who had participated in a single-dose PK study with FC 0.06 g kg-1 . RESULTS: A 1-compartment model with allometric scaling accounting for body weight was found to best describe the kinetics of FC. Addition of age and sex as covariates did not improve the model. Incremental in vivo recovery assessed at the end of infusion with the predicted maximal concentrations was lower, weight-adjusted clearance was higher, and fibrinogen elimination half-life was shorter in patients <40 kg than patients ≥40 kg. Interpatient variability was similar in both groups. CONCLUSION: Dosing in patients ≥40 kg based on the previous empirical finding using noncompartmental analysis where FC 1 g kg-1 raises the plasma fibrinogen activity by 23 g L-1 was confirmed. In patients <40 kg, (covering the age range from birth up to about 12 years old) FC 1 g kg-1 raises the plasma fibrinogen by 19 g L-1 . Dosing should be adapted accordingly unless therapy is individualized.

Clinical pharmacology, efficacy and safety study of a triple-secured fibrinogen concentrate in adults and adolescent patients with congenital fibrinogen deficiency.

Essentials A novel fibrinogen concentrate was evaluated in patients with congenital fibrinogen deficiency. An open-label, phase 2-3 trial studied pharmacology, efficacy, and safety in patients >6 years. The product offers safe and effective therapy in the treatment and prophylaxis of bleeding. Data in recovery show the need of adjusted treatment and further investigation in children. SUMMARY: Background Single-factor replacement therapy is considered the most suitable treatment option for hereditary fibrinogen deficiency. A triple-secured plasma-derived human fibrinogen product was developed to increase the safety of the former fibrinogen concentrate. Objectives This non-randomized, open-label, prospective study investigated pharmacokinetics, efficacy, and safety of a novel fibrinogen concentrate (FibCLOT® /CLOTTAFACT® LFB, France) in inherited deficiency. Patients/Methods Fourteen patients ≥40 kg received fibrinogen concentrate for pharmacology and 16 ≥ 23 kg received treatment for bleeding or surgery. Each treatment was followed by a 3-week safety observation period. Key outcomes included number of infusions, dose, bleeding control, daily assessment, hemoglobin, blood loss, transfusions, and physicians' global assessment of response. Results Incremental recovery was 2.35 mg mL-1  per mg kg-1 and maximal concentration 1.41 g L-1 (geometric mean) after 0.060 g kg-1 infusion in 14 afibrinogenemic patients. Terminal half-life was 69.3 h (non-compartmental analysis). The maximum clot firmness was increased by a mean of 10.3 mm from baseline to maximal effect. Sixteen patients participated to the efficacy phase: 32 bleeding episodes were treated in 9 patients, and 15 patients underwent 38 surgical/invasive procedures. All patients achieved appropriate hemostasis: response to treatment was successful in all bleeds (95% CI, 0.89-1.00) and procedures (95% CI, 0.91-1.00). Most (94%) bleeds were controlled with a single infusion (median 0.050 g kg-1 ). Two patients experienced asymptomatic distal venous thromboses identified by systematic ultrasound. Conclusion FibCLOT® /CLOTTAFACT® showed a pharmacokinetic profile comparable to that of other fibrinogen concentrates and provides safe and clinically effective substitution therapy for fibrinogen-deficient patients.