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A new population pharmacokinetic model for recombinant factor IX-Fc fusion concentrate including young children with
Sjoerd F Koopman1, Tine M H J Goedhart2, Laura H Bukkems1
1Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
Insights
A new pharmacokinetic model for recombinant factor IX Fc fusion protein (rFIX-Fc) in haemophilia B patients accurately predicts FIX activity, especially in children. This improves treatment monitoring for extended half-life factor concentrates.
Area of Science:
- Pharmacology
- Hematology
- Clinical Pharmacy
Background:
- Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate for haemophilia B.
- Existing pharmacokinetic (PK) models for rFIX-Fc are limited to patients aged 12 years and older.
Purpose of the Study:
- To externally evaluate the predictive performance of a published rFIX-Fc population PK model in patients of all ages.
- To develop a new population PK model for rFIX-Fc using real-world data to better describe its pharmacokinetics across different age groups.
Main Methods:
- Collected prospective and retrospective real-world data from 37 haemophilia B patients treated with rFIX-Fc.
- Assessed predictive performance by comparing predicted versus observed FIX activity levels.
- Constructed a new population PK model using nonlinear mixed-effects modeling.
Main Results:
- The published model significantly underpredicted FIX activity (median prediction error: -48.8%).
- The newly developed model demonstrated a substantially lower median prediction error (3.4%) and improved accuracy, particularly for children under 12 years.
- Increased age correlated with decreased clearance (P < .01) in the new model.
Conclusions:
- The published rFIX-Fc PK model is inadequate for predicting FIX activity across all age groups.
- A new population PK model provides a more accurate description of rFIX-Fc pharmacokinetics, especially in pediatric populations.
- Emphasizes the importance of developing representative PK models to avoid extrapolation and ensure accurate therapeutic monitoring.
Aims:
Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate 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 treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling.
Results:
Real-world data were obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of -48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P < .01).
Conclusions:
The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.
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