Xavier Delavenne1, Yesim Dargaud2, Edouard Ollier1, Claude Négrier2. 1. INSERM, UMR 1059, Dysfonction Vasculaire et de l'Hémostase, Université de Lyon, Saint Etienne, France. 2. Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, Université Lyon 1, Lyon, France.
Abstract
AIMS: The use of factor VIII (FVIII) prophylaxis in haemophilia A is considered the standard of care, particularly in children. Despite adjustment of doses for body weight and/or age, a large pharmacokinetic (PK) variability between patients has been observed. PK-tailored prophylaxis may help clinicians adjust coagulation factor FVIII activity (FVIII:C) to the desired level, which may differ in individual patients. The objective was to develop a population PK model for simoctocog alfa based on pooled clinical trial data and to develop a Bayesian estimator to allow PK parameters in individual patients to be estimated using a reduced number of blood samples. METHODS: PK data from 86 adults and 29 children/adolescents with severe haemophilia A were analysed. The FVIII data measured using 2 different assays (chromogenic and the 1-stage clotting assay) were fit to separate develop population PK models using nonlinear mixed-effect models. A Bayesian estimator was then developed to estimate the time above the threshold of 1%. RESULTS: The PK data for chromogenic and the 1-stage clotting assays were both best described by a 2-compartment models. Simulations demonstrated good predictive capacity. The limited sampling strategy using blood sample at 3 and 24 hours allowed an accurate estimation of the time above the threshold of 1% FVIII:C (mean bias 0.01 and 0.11, mean precision 0.18 and 0.45 for 2 assay methods). CONCLUSION: In this study, we demonstrated that a Bayesian approach can help to reduce the number of samples required to estimate the time above the threshold of 1% FVIII:C with good accuracy.
AIMS: The use of factor VIII (FVIII) prophylaxis in haemophilia A is considered the standard of care, particularly in children. Despite adjustment of doses for body weight and/or age, a large pharmacokinetic (PK) variability between patients has been observed. PK-tailored prophylaxis may help clinicians adjust coagulation factor FVIII activity (FVIII:C) to the desired level, which may differ in individual patients. The objective was to develop a population PK model for simoctocog alfa based on pooled clinical trial data and to develop a Bayesian estimator to allow PK parameters in individual patients to be estimated using a reduced number of blood samples. METHODS: PK data from 86 adults and 29 children/adolescents with severe haemophilia A were analysed. The FVIII data measured using 2 different assays (chromogenic and the 1-stage clotting assay) were fit to separate develop population PK models using nonlinear mixed-effect models. A Bayesian estimator was then developed to estimate the time above the threshold of 1%. RESULTS: The PK data for chromogenic and the 1-stage clotting assays were both best described by a 2-compartment models. Simulations demonstrated good predictive capacity. The limited sampling strategy using blood sample at 3 and 24 hours allowed an accurate estimation of the time above the threshold of 1% FVIII:C (mean bias 0.01 and 0.11, mean precision 0.18 and 0.45 for 2 assay methods). CONCLUSION: In this study, we demonstrated that a Bayesian approach can help to reduce the number of samples required to estimate the time above the threshold of 1% FVIII:C with good accuracy.
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