Design of a Prospective Study on Pharmacokinetic-Guided Dosing of Prophylactic Factor Replacement in Hemophilia A and B (OPTI-CLOT TARGET Study)

Goedhart, Tine M. H. J.; Bukkems, Laura H.; Coppens, Michiel; Fijnvandraat, Karin; Schols, Saskia E. M.; Schutgens, Roger E. G.; Eikenboom, Jeroen; Heubel‐Moenen, Floor C. J. I.; Ypma, Paula F.; Nieuwenhuizen, Laurens; Meijer, Karina; Leebeek, Frank W.G.; Mathôt, Ron A. A.; Cnossen, Marjon H.

doi:10.1055/a-1760-0105

Cited by 4 publications

(3 citation statements)

References 37 publications

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“…The trial is registered at the Dutch Trial register under trial number NTR7523 ( www.trialregister.nl ). OPTI-CLOT TARGET study design and detailed methods with figures have been described in an earlier publication [ 20 ]. People of all ages with hemophilia A and B on prophylaxis—both weight-based or PK-guided—or starting prophylaxis using SHL or EHL factor concentrates were eligible.…”

Section: Methodsmentioning

confidence: 99%

Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B

Goedhart,

Bukkems,

Zwagemaker

et al. 2024

Research and Practice in Thrombosis and Haemostasis

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Section: Methodsmentioning

confidence: 99%

Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B

Goedhart,

Bukkems,

Zwagemaker

et al. 2024

Research and Practice in Thrombosis and Haemostasis

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“…We collected data from haemophilia B patients treated prophylactically with rFIX‐Fc (eftrenonacog alfa, Alprolix, GtoPdb Ligand ID 7373 17 ) included in the OPTI‐CLOT TARGET study 18 or UK‐EHL Outcomes Registry (NCT02938156). Ethical approval and written informed consent were obtained.…”

Section: Methodsmentioning

confidence: 99%

A new population pharmacokinetic model for recombinant factor IX‐Fc fusion concentrate including young children with haemophilia B

Koopman,

Goedhart,

Bukkems

et al. 2023

Brit J Clinical Pharma

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BackgroundRecombinant 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.AimExternally 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.MethodsWe 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 new population PK model was constructed using nonlinear mixed‐effects modelling.ResultsReal 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 eror (MdPE) of ‐48.8%. The new model showed a lower MdPE (3.4%) and better described rFIX‐Fc PK, especially for children <12 years of age. In the new model, an increase in age was correlated with a decrease in clearance (p<0.01).ConclusionThe published population PK model significantly underpredicted FIX activity levels. The new 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.

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“…We collected data from haemophilia B patients (endogenous FIX activity level [?] 5 IU/dL) treated with rFIX-Fc (eftrenonacog alfa, Alprolix(r)) included in the OPTI-CLOT TARGET study (NTR7523) 17 or United Kingdom (UK)-EHL Outcome Registry (NCT02938156). Briefly, haemophilia patients in the OPTI-CLOT TARGET study received nine months of PK-guided dosing to investigate the reliability and feasibility of the Bayesian forecasting procedure.…”

Section: Data Collectionmentioning

confidence: 99%

A novel population pharmacokinetic model for recombinant factor IX-Fc fusion concentrate including young children with haemophilia B

Koopman,

Goedhart,

Bukkems

et al. 2023

Preprint

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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.

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Design of a Prospective Study on Pharmacokinetic-Guided Dosing of Prophylactic Factor Replacement in Hemophilia A and B (OPTI-CLOT TARGET Study)

Cited by 4 publications

References 37 publications

Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B

Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B

A new population pharmacokinetic model for recombinant factor IX‐Fc fusion concentrate including young children with haemophilia B

A novel population pharmacokinetic model for recombinant factor IX-Fc fusion concentrate including young children with haemophilia B

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