Personalization of hemophilia treatment by pharmacokinetic-guided dosing

Hemophilia A and B are caused by a deficiency of coagulation factor VIII (FVIII) and IX (FIX), respectively. This deficiency results in impaired hemostasis and, hence, leads to bleeding in joints and muscle. Patients with severe hemophilia administer prophylactic doses of factor concentrate several times a week. In the surgical situation, hemophilia patients receive high doses of factor concentrate. In both cases, the observed factor levels in blood differ substantially between patients, despite adjustment of doses on the basis of bodyweight. These differences are caused by variability in the individual pharmacokinetic (PK) parameters. Therefore, this thesis aimed to investigate the personalization of hemophilia treatment by application of PK-guided dosing. In PK-guided dosing, individual PK parameters are estimated by applying maximum a posteriori Bayesian analysis. A population PK model allows to perform Bayesian analysis using a limited number (2 to 3) of observations, which is beneficial in clinical practice. In this thesis, population PK models were developed describing the time profiles of FVIII and FIX levels in pediatric and adult hemophilia patients during surgery. Moreover, it was shown that the PK of FVIII in the peri-surgical situation differed from the prophylactic situation and that dedicated population PK models should be applied when performing PK-guided dosing. Therefore, this thesis provided novel insights into the PK of factor concentrates used in the treatment of adult and pediatric hemophilia A and B patients during prophylaxis or surgery. These results contribute to the personalized treatment of hemophilia A and B patients using factor concentrates.