Innovating the treatment of inherited bleeding disorders by pharmacokinetic- and pharmacodynamic-guided dosing

Hemophilia A, hemophilia B and von Willebrand disease (VWD) are inherited bleeding disorders that are mostly treated with factor concentrates to prevent bleeding. When persons receive the same factor concentrate dose per kilogram bodyweight, large differences in achieved factor levels are observed in the blood due to inter-individual differences in pharmacokinetics (PK). A potential solution to more adequate dosing of these concentrates is found in PK-guided dosing. Herewith, the dose is tailored to the individual by application of maximum a priori (MAP) Bayesian forecasting. To apply MAP Bayesian forecasting and estimate individual PK parameters, population PK models should be available. Studies in this thesis describe the development of population PK models for clotting factor concentrates applied in hemophilia and VWD. Moreover, in a prospective study we observed that the predictive performance of PK-guided prophylactic dosing with factor concentrates is adequate in clinical practice for persons with hemophilia.
Importantly, during prophylactic therapy hemophilia patients with similar clotting factor levels in the blood exhibit a different bleeding tendency. The latter demonstrates inter-individual variability in bleeding phenotypes (pharmacodynamics (PD)). An innovative and alternative approach could be to dose factor concentrates based on both PK and PD parameters, as this may lead to further improvement in dosing personalization. In this thesis, we present the first steps to support dosing based on PK and PD parameters for persons with hemophilia. We developed population PK/PD models that describe the relationship between factor levels and the individual hemostatic potential or the individual bleeding risk.
In conclusion, the results of this thesis contribute to personalized treatment of persons with hemophilia and VWD.