INTRODUCTION
Haemophilia B is an inherited bleeding disorder caused by mutations in
the F9 -gene on the X-chromosome1. These
mutations result in a coagulation factor IX (FIX) deficiency, leading to
impaired haemostasis. Severely and moderately affected haemophilia B
patients suffer from spontaneous bleeding or bleeding after minor
trauma, especially into joints and muscles. When left untreated, these
bleeds may be life-threatening or lead to arthropathy with ultimately
long-term disability2. FIX replacement therapy - both
prophylactically and on demand - is mainstay of treatment, leading to a
normal life expectancy with good quality of life3.
Extended half-life (EHL) FIX concentrates have further ameliorated the
burden of disease by substantially decreasing the frequency of
intravenous FIX concentrate administration to on average once every
week4.
Recombinant factor IX Fc fusion protein (rFIX-Fc) is an EHL-FIX
concentrate which consists of a single recombinant FIX molecule fused to
the dimeric Fc domain of human immunoglobulin G1
(IgG1)5. This fusion delays the lysosomal degradation
by recycling rFIX-Fc back into circulation. As a result, half-life is
prolonged from 17h for rFIX to 82h for rFIX-Fc in patients ≥12 years of
age4. The pharmacokinetics (PK) of FIX concentrates
are complex and demonstrate a high level of interindividual variability
(IIV)6–9. As a result, FIX activity levels vary
substantially between patients10–12. The variability
in PK parameters of individual subjects entails individual adjustments
for administration of FIX replacement therapy by application of Bayesian
forecasting. This application using population PK models has been shown
to be successful to individualize factor concentrate dosing in
haemophilia treatment13,14. Furthermore, Bayesian
forecasting methodology allows for limited sampling in contrast to
traditional modelling methods15.
To establish the PK characteristics of rFIX-Fc and identify covariates,
Diao et al. developed a rFIX-Fc three-compartment population PK
model16 using data from several clinical trials. To
our knowledge, this is the only population PK model currently published
for this EHL factor concentrate. Importantly, this model has not been
externally validated. Moreover, this model was constructed using data of
only a limited number (n = 11) of children, all ≥12 and <18
years of age. Therefore, the accuracy of this model in children
<12 years of age may be limited. The aim of this study is to
validate and assess the predictive performance of the published rFIX-Fc
model using new independent real world patient data. The secondary aim
is to develop a novel population PK model describing the PK in a more
extended age range, including children <12 years of age.