Pharmacokinetics, clot strength and safety of a new fibrinogen concentrate: randomized comparison with active control in congenital fibrinogen deficiency

Background: Human fibrinogen concentrate (HFC) corrects fibrinogen deficiency in congenital a-/hypofibrinogenemia. Objectives: To assess pharmacokinetics (PK), effects on thromboelastometry maximum clot firmness (MCF), and safety of a new double virusinactivated/eliminated, highly purified HFC vs. active control. Patients/Methods: In this multinational, randomized, phase II, open-label, crossover study in 22 congenital afibrinogenemia patients aged >= 12 years, 70 mg kg(-1) of new HFC (FIBRYGA, Octapharma AG) or control (Haemocomplettan (R) P/RiaSTAP (TM), CSL Behring GmbH) were administered, followed by crossover to the other concentrate. Fibrinogen activity, PK and MCF in plasma were assessed. Results: The concentrates were not bioequivalent for the primary endpoint, AUC(norm) (mean ratio, 1.196; 90% confidence interval [CI], 1.117, 1.281). Remaining PK parameters (C-maxnorm, IVR, t(1/2), MRT) reflected bioequivalence between concentrates, except for clearance (mean ratio, 0.836; 90% CI, 0.781, 0.895) and V-ss (mean ratio, 0.886; 90% CI, 0.791, 0.994). Mean AUC(norm) was significantly larger for the new HFC (1.62 +/- 0.45 vs. 1.38 +/- 0.47 h kg g L-1 mg(-1), P = 0.0001) and mean clearance was significantly slower (0.665 +/- 0.197 vs. 0.804 +/- 0.255 mL h(-1) kg(-1), P = 0.0002). Mean MCF increased from 0 mm to 9.68 mm (new HFC) and 10.00 mm (control) 1-hour post-infusion (mean difference, -0.32 mm; 95% CI, -1.70, 1.07, n.s.). No deaths, thromboses, viral seroconversions or serious related adverse events occurred. Conclusions: Bioequivalence was not demonstrated for AUC(norm), clearance and V-ss. Larger AUC(norm) and slower clearance were observed for the new HFC. Remaining pharmacokinetic parameters reflected bioequivalence to control. Safety profiles and increases in clot strength were comparable between concentrates.