Borella, Elisa;
Oosterholt, Sean;
Magni, Paolo;
Pasqua, Oscar Della;
(2022)
Characterisation of individual ferritin response in patients receiving chelation therapy.
British Journal of Clinical Pharmacology
10.1111/bcp.15290.
(In press).
Preview |
Text
Della Pasqua_Brit J Clinical Pharma - 2022 - Borella - Characterisation of individual ferritin response in patients receiving chelation.pdf Download (1MB) | Preview |
Abstract
AIM: To develop a drug-disease model describing iron overload and its effect on ferritin response in patients affected by transfusion-dependent haemoglobinopathies and investigate the contribution of interindividual differences in demographic and clinical factors on chelation therapy with deferiprone or deferasirox. METHODS: Individual and mean serum ferritin data were retrieved from 13 published studies in patients affected by hemoglobinopathies receiving deferiprone or deferasirox. A nonlinear mixed effects modelling approach was used to characterise iron homeostasis and serum ferritin production taking into account annual blood consumption, baseline demographic and clinical characteristics. The effect of chelation therapy was parameterised as an increase in the iron elimination rate. Internal and external validation procedures were used to assess model performance across different study populations. RESULTS: An indirect response model was identified, including baseline ferritin concentrations and annual blood consumption as covariates. The effect of chelation on iron elimination rate was characterised by a linear function, with different slopes for each drug [0.0109 (90% CI: 0.0079-0.0131) vs. 0.0013 (90% CI: 0.0008-0.0018) L/mg.month]. In addition to drug-specific differences in the magnitude of the ferritin response, simulation scenarios indicate that ferritin elimination rates depend on ferritin concentrations at baseline. CONCLUSIONS: Modelling of serum ferritin following chronic blood transfusion enabled the characterisation of drug-induced changes in iron elimination rate and ferritin production. The use of a semi-mechanistic parameterisation allowed us to disentangle disease-specific factors from drug-specific properties. Despite comparable chelation mechanisms, deferiprone appears to have a significantly larger effect on the iron elimination rate than deferasirox.
| Type: | Article |
|---|---|
| Title: | Characterisation of individual ferritin response in patients receiving chelation therapy |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/bcp.15290 |
| Publisher version: | https://doi.org/10.1111/bcp.15290 |
| Language: | English |
| Additional information: | © 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
| Keywords: | chelating agents, deferasirox, deferiprone, disease modelling, ferritin, pharmacokinetic-pharmacodynamic relationships, thalassaemia |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10144676 |
Archive Staff Only
 |
View Item |
