Use of population PK/PD approach to model the thrombin generation assay: assessment in haemophilia A plasma samples spiked by a TFPI antibody

AbstractThe thrombin generation (TG) assay is a well-established tool to capture the clotting potential of any healthy or haemophiliac subject. It measures ex vivo the kinetics of thrombin activation throughout the coagulation. Clinical studies allowed to create two databases gathering the coagulation factor levels and the thrombin generation profile of 40 healthy and 40 haemophiliac A (HA) subjects. Besides, portions of all HA samples were spiked with increasing levels of a TFPI antibody (considered as a possible therapeutic target) and corresponding TG profiles were determined. The non-linear mixed-effect (NLME) modelling aims at describing and explaining the experimentally observed important variability of the TG curves between subjects and the individual effects of spiking with a TFPI antibody. The models consist of an empirical description of the TG kinetics, accounting for an additive residual error and between-subject variability on its parameters. Factor VIII and TFPI were found to significantly explain and reduce the variability of the TG of haemophilia A samples. Besides, the model is shown to correctly reproduce the variability in the response to the ex vivo spiking with the TFPI antibody, by combining the empirical description of TG to a simple Hill equation that accounts for the binding between TFPI and different doses of its antibody. Such models can be useful for clinical practice, with the analysis and comparison of the distributions of TG profiles in healthy ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research