Abstract
PurposeHere we show how a model-based approach may be used to provide further insight into the role of clinical and demographic covariates on the progression of iron overload. The therapeutic effect of deferoxamine is used to illustrate the application of disease modelling as a means to characterising treatment response in individual patients.MethodsSerum ferritin, demographic characteristics and individual treatment data from clinical routine practice on 27 patients affected by β-thalassaemia major were used for the purposes of this analysis. The time course of serum ferritin was described by a hierarchical nonlinear mixed effects model, in which compliance was parameterised as a covariate factor. Modelling and simulation procedures were implemented in NONMEM (7.2.0).ResultsA turnover model best described serum ferritin changes over time, with the effect of blood transfusions introduced on the ferritin conversion rate and the effect of deferoxamine on the elimination parameter (Kout) in a proportional manner. The results of the simulations showed that poor quality of execution is preferable over drug holidays; and that independently of the compliance pattern, the therapeutic intervention is not effective if >60% of the doses are missed.ConclusionsModelling of ferritin response enables characterisation of the dynamics of iron overload due to chronic transfusion. The approach can be used to support decision making in clinical practice, including personalisation of the dose for existing and novel chelating agents.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-015-1805-0) contains supplementary material, which is available to authorised users.
Highlights
Beta-thalassaemia major is a hereditary blood disorder and patients affected by this disease require regular red blood cell (RBC) transfusions to survive [1,2,3,4,5,6,7]
We show how modelling and simulation (M&S) can be applied to support decision making in clinical practice providing a framework to predict changes in the disease status and the evaluate the impact of predefined therapeutic regimens
As described in the methods a disease model was previously developed for iron overload [unpublished results] and its performance in describing the impact of blood transfusions on serum ferritin was confirmed in this analysis
Summary
Transfusional Iron OverloadBeta-thalassaemia major is a hereditary blood disorder and patients affected by this disease require regular red blood cell (RBC) transfusions to survive [1,2,3,4,5,6,7]. For a complex process such as iron overload, understanding of the dynamics of the disease and its progression is crucial to adequately evaluate the impact of a therapeutic intervention This complexity is characterised by the fact that the biomarker ferritin does not provide a direct link between total body or tissue iron accumulation at specific time points. The absence of such a relationship is partly explained by the influence of other pathological mechanisms (e.g., inflammatory disorders, and/or liver status) which can affect the iron interchange between organs and the circulatory system [2,12,13,14]. Several clinical questions are not yet fully explored, e.g., how much time is required in order to observe a true response, or in order to reach clinically safe serum ferritin levels
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