Abstract
Drug therapy is an important component of the treatment and prevention of diseases. A drug is administered to achieve a treatment target so it is important to quantify the drug dose and dosing regimen prior to administration in order to achieve this target. Following administration, the patient’s response to therapy is assessed and the drug dosage is adjusted accordingly in order to optimise therapy in terms of effectiveness and safety. The process of obtaining a treatment target for a particular drug, calculating a suitable dosage for an individual patient, measuring patient response, and adjusting dosage in order to optimise this response is complex and often inadequately done in clinical practice. This process often requires specialised knowledge in drug pharmacokinetics, pharmacodynamics, and model-based dose individualisation.
In this thesis a treatment target for the anticoagulant drug enoxaparin was explored. The target (anti-factor Xa) was evaluated using a Bayesian dose-individualisation method and data collected retrospectively. The Bayesian forecasting method was then applied prospectively in a randomised clinical trial. Also, the analytical method used to measure enoxaparin concentration (anti-factor Xa) was evaluated in terms of accuracy, precision, stability, and performance in special conditions such as blood sample haemolysis and antithrombinaemia.
The thesis also explored one of the main sources of variability in response between individuals, body composition. A model to predict fat-free mass, as a measure of structural maturation, from age, sex, height, and weight was developed and evaluated. The maturation model was then used successfully to develop a pharmacokinetic-pharmacodynamic model for the anticoagulant drug unfractionated heparin in a paediatric population.