Factor IX gene variants may influence the pharmacokinetic profile of patients with hemophilia B treated with Factor IX-fusion protein or N9-GP extended half-life Factor IX concentrates.

BACKGROUND: Factor IX (FIX) exhibits significant extravascular distribution and binds type IV collagen in the subendothelial extracellular matrix in the extravascular space, which influences its function and pharmacokinetics (PK). Many hemophilia B patients carry missense F9 mutations that produce circulating, dysfunctional FIX protein [cross-reacting material; (CRM)]. In murine hemophilia models, the presence (CRM+) or absence (CRM-) of dysfunctional FIX modifies the PK and hemostatic efficacy of exogenous FIX. We hypothesized that the PK parameters of extended half-life (EHL) FIX products that have a significant (Fc-FIX) or negligible extravascular distribution might be differently influenced by the presence of endogenous FIX antigen in the vascular and extravascular space.

AIM: To investigate the association of F9 variants and the individual PK profile of patients treated with EHL FIX concentrates.

METHODS: Individual PK profiles were extracted from the WAPPS-Hemo database, and causal F9 mutations were sourced from linked databases. Differences in PK parameters between CRM+ and CRM- groups were analyzed.

RESULTS: Seventy individuals treated with EHL FIX, with known PK profile and gene mutation were included. Among rFIX-Fc recipients, CRM+ patients had significantly lower clearance, longer terminal half-life, higher in vivo recovery, and smaller volume of distribution. No significant PK differences were found between CRM+ and CRM- patients receiving N9-GP.

CONCLUSIONS: The pharmacokinetics of EHL FIX products are influenced by their ability to access the extravascular space. For products with substantial extravascular distribution, patient CRM status further modulates PK behavior.