Giammarco Baiardi (1,2), Francesca Mattioli (1,2), Natalia Maximova (3), Alessandro Di Deo (4), Salvatore D’Agate (4), Oscar Della Pasqua (4)
(1) Pharmacology & Toxicology Unit, Department of Internal Medicine, University of Genoa, Viale Benedetto XV 2, 16132 Genoa, Italy, (2) Clinical Pharmacology Unit, Ente Ospedaliero Ospedali Galliera, Mura Delle Cappuccine 14, 16128 Genoa, Italy, (3) IRCCS Burlo Garofolo, Bone Marrow Transplant Unit, Institute for Maternal and Child Health, 34137 Trieste, Italy, (4) Clinical Pharmacology & Therapeutics Group, University College London, BMA House, Tavistock Square, London, WC1H 9JP, United Kingdom
Introduction: Iron overload (IO) is common in adults and children with malignancies undergoing allogeneic haematopoietic stem cell transplantation (aHSCT) due to prior transfusion burden [1]. Early and late post-transplant iron toxicity due to IO can have a negative impact on aHSCT success by the disruption of bone marrow and systemic organs’ function [2-3]. Although phlebotomy is recommended to reduce iron burden, this procedure may not be feasible in these patients. Indeed, iron excess can impair HSC engraftment early after transplant and delay anaemia recovery [3]. Conversely, iron chelation therapy has been shown to improve aHSCT outcomes in this setting and several guidelines recommend treatment with deferasirox (DFX) in patients who underwent an intensive transfusion regimen [4-5]. However, the dose rationale for maximum reduction of the transfusional burden has not been established. When iron chelators are used, the starting dose is reduced to 50% of the currently approved dose (i.e., 7 or 10 mg/kg dose for film-coated or dispersible tablet, respectively) [5]. The dose can then be carefully increased with close monitoring of hepatic and renal function, but no attention is given the interindividual differences in exposure to chelators or IO. Despite the lack of a correlation between IO reduction and currently recommended DFX dosing regimens, trough concentration at steady-state (Ctrough,ss) < 10 μg/mL has been proposed as a reference threshold based on clinical evidence of a lower adverse event incidence [6].
Objectives: To characterise the population pharmacokinetics of DFX in paediatric patients undergoing aHSCT and identify an optimised DFX dosing regimen that takes into account patient baseline characteristics known to affect drug disposition and ferritin homeostasis.
Methods: Initially, the pharmacokinetics of DFX was characterised in a population of children (n=36) affected by haematological malignancies and subjected to aHSCT. Final parameter estimates were then used to simulate the impact of different DFX regimens on exposure and subsequently on serum ferritin profiles over the course of therapy. Optimisation criteria focused first on the identification of starting doses that are associated with low incidence of adverse events (Ctrough,ss < 10 μg/mL). This was followed by an evaluation of up-titration steps that maximise serum ferritin reduction using a previously published drug-disease model describing the effects of iron chelation on serum ferritin [7]. Finally, simulation scenarios were implement taking into account a wider paediatric patient population. Standard diagnostics, graphical and statistical criteria were used for model evaluation. All modelling and simulation procedures were implemented in NONMEM v7.5./Pirana, whilst R version 4.3.2 was used for data formatting, graphical and statistical summaries.
Results: A two-compartmental model with first-order absorption and first-order elimination best described the pharmacokinetics of DFX in paediatric aHSCT patients. Body weight scaled by allometric principles was identified as significant covariate influencing DFX disposition. A starting dose of 7 or 10. 5 mg/kg was identified for patients weighting > 30 kg or <30 kg, which guarantees concentrations within the well-tolerated exposure range. Simulation scenarios have shown the implications of DFX-induced ferritin reduction over 24 months post transfusion regimen and the importance of up-titration to the maximum approved dose for effective chelation.
Conclusion: Starting doses DFX were identified, which are likely to minimise adverse events and drug-induced tolerability issues. However, chelation therapy should proceed with titration steps of 3.5 mg/kg up to 28 m/kg, taking into account ferritin levels at baseline. In addition, monitoring of DFX concentrations and serum ferritin shortly after initiation of treatment may offer an opportunity to assess the probability adverse events and establish up-titration requirements for effective iron chelation. These steps may also eliminate the need short term assessment of liver iron concentrations through magnetic resonance imaging or by chemical analysis of needle biopsy specimens. Further in silico evaluation of the effect of deferiprone on IO in aHSCT patients should be considered as an alternative for patients who show poor tolerability to DFX or have high ferritin levels at baseline.
[1] Isidori, Alessandro et al. “Iron Toxicity and Chelation Therapy in Hematopoietic Stem Cell Transplant.” Transplantation and cellular therapy vol. 27,5 (2021): 371-379. doi:10.1016/j.jtct.2020.11.007
[2] Angelucci, E., & Pilo, F. (2016). Management of iron overload before, during, and after hematopoietic stem cell transplantation for thalassemia major. Annals of the New York Academy of Sciences, 1368(1), 115–121. https://doi.org/10.1111/nyas.13027
[3] Cattoni, Alessandro et al. “Iron Overload Following Hematopoietic Stem Cell Transplantation: Prevalence, Severity, and Management in Children and Adolescents with Malignant and Nonmalignant Diseases.” Transplantation and cellular therapy vol. 29,4 (2023): 271.e1-271.e12. doi:10.1016/j.jtct.2023.01.020
[4] Jaspers, Aurélie et al. “Évaluation et prise en charge de la surcharge en fer post-greffe : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)” [Assessment and management of post-transplant iron overload: Guidelines of the Francophone Society of Marrow Transplantation and Cellular Therapy (SFGM-TC)]. Bulletin du cancer vol. 103,11S (2016): S255-S266. doi:10.1016/j.bulcan.2016.09.003
[5] Nava, Tiago et al. “Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).” Bone marrow transplantation vol. 55,6 (2020): 1126-1136. doi:10.1038/s41409-020-0818-4
[6] Maximova, Natalia et al. “Safety and tolerability of deferasirox in pediatric hematopoietic stem cell transplant recipients: one facility’s five years’ experience of chelation treatment.” Oncotarget vol. 8,38 63177-63186. 28 Jun. 2017, doi:10.18632/oncotarget.18725
[7] Borella, Elisa et al. “Characterisation of individual ferritin response in patients receiving chelation therapy.” British journal of clinical pharmacology vol. 88,8 (2022): 3683-3694. doi:10.1111/bcp.15290
Reference: PAGE 32 (2024) Abstr 10965 [www.page-meeting.org/?abstract=10965]
Poster: Drug/Disease Modelling - Paediatrics