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.