On the development of pharmacokinetic models for the characterisation and diagnosis of von Willebrand disease

Abstract Von Willebrand disease (VWD) is a metabolic disease characterised by a qualitative and/or quantitative deficiency of von Willebrand factor (VWF) a multimeric glycoprotein that mediates platelet adhesion in haemostatic processes. Pharmacokinetic (PK) models have been developed to characterise VWD metabolic pathways and to achieve a model-based diagnosis based on clinical data. However, current PK models cannot be calibrated from infusion tests data, and their calibration requires stressful 24-h long tests to be carried out on subjects to achieve a statistically satisfactory estimation of the individual haemostatic parameters. The objectives of this review chapter are the following: i ) to provide a review on physiological modelling of VWD starting from the analysis of basic VWF mechanisms in the body; ii ) to describe methods and modelling tools used to provide a model-based diagnosis of VWD and, consequently, a classification of complex VWD types; iii ) to illustrate how model-based design of experiments (MBDoE) techniques can be applied to maximise the information that can be obtained from advanced clinical tests (DDAVP) but also from infusion tests used in VWD treatment where blood analogues are administered through single or multiple injections. Results show how PK models calibrated from clinical data can be used to estimate key haemostatic parameters in the diagnosis of the disease. Promising results on the application of MBDoE to design infusion tests show how the duration of clinical tests for the identification of key haemostatic parameters can significantly be reduced from 24 h to 2.5 h, with the potential to increase the acquired test information if multiple infusions can be managed.