Factor IX gene variants may influence the pharmacokinetic profile of patients with hemophilia B treated with FIX-Fc or N9-GP extended half-life FIX concentrates.
BACKGROUND 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 EHL FIX products that have a significant (Fc-FIX) or negligible (PEG-FIX) 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 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 pharmacokinetic behaviour.