Model-based Individualized Drug Therapy

Siv Jönsson, Mats Karlsson, Elisabet Nielsen

Variability in pharmacokinetics and pharmacodynamics are common and might result in suboptimal treatment in the individual patient. In our research we aim to facilitate model-based treatment individualization and advance the methodologies used for dose individualization based on therapeutic drug monitoring (TDM). Ongoing projects relate to dose individualization of antibiotics in critically ill patients, levodopa treatment in patients with Parkinson’s disease and Factor VIII replacement therapy in Haemophilia A patients.

Hemophilia is a group of hereditary genetic disorders impairing blood coagulation. Hemophilia A and B refer to the coagulation factor VIII and IX deficiency, respectively, whereof hemophilia A is the more common although rare: in Sweden 14 of 100 000 boys and men have hemophilia, whereof 80 % has hemophilia A. By substitution therapy with the coagulation factors, on-demand or prophylactically, the disease status can be controlled. In prophylactic treatment of factor VIII and IX, pharmacokinetic (PK) tailored dose individualization, i.e. the individual dose is based on Bayesian estimation using pharmacokinetic information and a population PK model, is promoted and appears to be a good approach for reducing the total doses administered. We are involved in a clinical study where the benefit of PK tailored dosing for prophylactic FVIII treatment is evaluated in clinical practice. Our contribution in the project refers to the Bayesian estimation of the dose. We will also explore alternative approaches in the dose individualization involving exposure-response models. Furthermore, for factor IX we have re-developed a population PK model and, based on the model, explored alternative clinical practically sampling schedules to be used in PK tailoring.