12 March 2018 from 10:30 to 11:30

PhD defence of Kimberley Span

Therapeutic iron: Evaluation of methods to assess intravenous iron safety profiles and the development of a novel formulation for oral iron delivery

Iron treatment is necessary to replenish iron deficit due to several clinical conditions such as chronic diseases. However, as an excess of iron can result in redox imbalance resulting in oxidative stress and thus severe damage to tissue and organs, it is of utmost importance to develop iron therapies that are effective and yet safe to not induce iron overload.  Especially in the case of intravenous iron formulations, several factors such as the physicochemical properties and manufacturing processes have demonstrated to impact their efficiency and safety invivo. Up to date it has been a challenge to develop evaluation methods, particularly suitable in vivopre-clinical models to perform proper comparisons and in-depth assessment studies of iron therapeutics. It is therefore of utmost importance to develop and define sensitive evaluation methods when original iron formulations with generics are compared from a pharmaceutical point of view. Several non-clinical animal studies have been previously published with the aim to compare the original intravenous iron sucrose product to new iron sucrose similars (generics). The objective of this thesis was to evaluate non-clinical in vivo models that aim to assess safety profiles of intravenous iron products, as these methods are not easy to standardize and the outcomes of the various studies are not in agreement. Furthermore, as characterization of the physicochemical properties (e.g. size, charge, stability) of an intravenous iron preparation is not predictive for the clinical effect of the injected iron formulation, an assessment of the iron distribution in vivo was done using Magnetic Resonance Imaging (MRI).

The results presented in this thesis demonstrate, the difficulties to compare, standardize and reproduce results from various pre-clinical iron related comparison studies that were performed with similar experimental design including a similar animal model. In addition after investigating whether a frequently used animal strain for these purposes is actually sensitive enough, it remained questionable whether this model is really able to give proper insight into possible toxic effects and biodistribution of various iron formulations.  Furthermore, it was interesting to investigate other possible methods such as Magnetic Resonance Imaging (MRI) to obtain further insight into the iron biodistribution after intravenous iron administration. The MRI technique has proven to be a powerful non-invasive modality to monitor iron distribution after administering exogenous iron. 

Start date and time
12 March 2018 10:30
End date and time
12 March 2018 11:30
PhD candidate
K. (Kimberley) Span
Dissertation
Therapeutic iron: Evaluation of methods to assess intravenous iron safety profiles and the development of a novel formulation for oral iron delivery
PhD supervisor(s)
prof.dr.ir. W.E. Henninkprof.dr. H. Schellekens
Co-supervisor(s)
dr. V. Brinks