A novel population pharmacokinetic model for recombinant factor IX-Fc
fusion concentrate including young children with haemophilia B
Abstract
Background Recombinant factor IX Fc fusion protein (rFIX-Fc) is an
extended half-life (EHL) factor concentrate administered to haemophilia
B patients. So far, a population pharmacokinetic (PK) model has only
been published for patients ≥12 years of age. Aim Assess the predictive
performance of the published rFIX-Fc population PK model for patients of
all ages and develop a model that describes rFIX-Fc PK using real world
data. Methods We collected prospective and retrospective data from
patients with haemophilia B (FIX activity level ≤5 IU/dL) treated with
rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United
Kingdom (UK)-EHL Outcome Registry (NCT02938156). Predictive performance
was assessed by comparing predicted with observed FIX activity levels. A
novel population PK model was constructed using nonlinear mixed-effects
modelling. Results Real world data was obtained from 37 patients (median
age: 16 years, range 2-71) of whom 14 were <12 years of age.
Observed FIX activity levels were significantly higher than levels
predicted using the published model, with a median prediction error (PE)
of -48.8%. The novel model showed a lower median PE (3.4%) and better
described rFIX-Fc PK, especially for children <12 years of
age. In the novel model, an increase in age was correlated with a
decrease in clearance (p<0.01). Conclusion The published
population PK model significantly underpredicted FIX activity levels.
The novel model better describes rFIX-Fc PK, especially for children
<12 years of age. This study underlines the necessity to
strive for representative population PK models, thereby avoiding
extrapolation outside the studied population.