Alessandro Di Deo (1), Sean Oosterholt (1), Elisa Borella (2), Paolo Magni (2), Oscar Della Pasqua (1)
(1) Clinical Pharmacology & Therapeutics Group, University College London, London, UK, (2) Dipartimento di Ingegneria Industriale e dell’Informazione, University of Pavia, Pavia, IT
Objectives: Haemoglobinopathies are a group of inherited disorders characterized by structural variations of the haemoglobin molecule which often lead to ineffective erythropoiesis. Frequent blood transfusions are the recommended treatment to suppress ineffective erythropoiesis and to provide adequate oxygen carrying capacity. Patients become iron overloaded within 3 to 24 months of a transfusion regimen aimed to maintain a minimum haemoglobin (Hb) concentration of 9.5 to 10.5 g/dL. Deferasirox is a once-daily orally active iron chelator currently approved for the treatment of transfusion dependent chronic iron overload (≥ 7 ml/kg/month of packed red blood cells) and is widely used in the paediatric population. Despite its known efficacy and safety profile, there are very limited data on the pharmacokinetics of deferasirox in children. In fact, it is unclear whether systemic exposure after therapeutic doses between 20 and 40 mg/kg are comparable across the paediatric population, after correcting for the effect of body weight.
Methods:
A model-based meta-analytical approach was used to characterise the population pharmacokinetics of deferasirox using data extracted from five published PK studies including adult healthy subjects as well as adult and paediatric patients [1-5]. Given the limited data availability across the different age subgroups, allometric principles were used to describe the effect of body weight on drug disposition[6].. Model diagnostics and predictive performance were evaluated using graphical and statistical criteria. Subsequently, predictive performance was assessed by external validation. Pharmacokinetic data from paediatric patients affected by transfusion-dependent haemoglobinopathies receiving deferasirox for a period of 12 months were available for the purposes of this investigation. In total, one single blood sample for each of the 63 patients with a median age of 8.8 (range: 1.4 – 17.5) years and a median weight of 25.5 (range: 9.5 – 67.7) kg was collected and included in the analysis. Visual predictive checks (VPC), including median, 5th and 95th percentiles of the simulated data were compared to the same percentiles of the observed data to establish model performance in in this population. Modelling and simulation steps were implemented using a nonlinear mixed effects approach, as implemented in NONMEM v. 7.3. Model validation and data handling was performed using R v.3.4.4.
Results: A two-compartment pharmacokinetic model with first order absorption and first order elimination was used to describe the concentration vs. time profiles in adults and children. Interindividual variability was identified for all structural model parameters except for intercompartmental clearance. Population parameter estimates for absorption rate constant, clearance, central volume of distribution and intercompartmental clearance were 0.119 h-1, 1.74 L/h, 21.3 L, 1.95 L/h, respectively. Binning of exposure across different weigh bands (toddlers, children, adolescents) showed that differences in exposure across the age range may be clinically relevant. The external validation data were accurately described by the model, providing further insight into the disposition of deferasirox in children.
Conclusions: The use of a model-based meta-analytical approach showed that the PK of deferasirox can be extrapolated to the paediatric population using allometric principles. These results provide the basis for future investigations in which sparse blood sampling will be used to describe the effect of chelation on ferritin levels and establish whether there are age-related differences in iron homeostasis.
References:
[1] Chirnomas, D., et al., Deferasirox pharmacokinetics in patients with adequate versus inadequate response. Blood, 2009. 114(19): p. 4009-13.
[2] Miyazawa, K., et al., A safety, pharmacokinetic and pharmacodynamic investigation of deferasirox (Exjade, ICL670) in patients with transfusion-dependent anemias and iron-overload: a Phase I study in Japan. Int J Hematol, 2008. 88(1): p. 73-81.
[3] Sechaud, R., et al., Absolute oral bioavailability and disposition of deferasirox in healthy human subjects. J Clin Pharmacol, 2008. 48(8): p. 919-25.
[4] Waldmeier, F., et al., Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state. Drug Metab Dispos, 2010. 38(5): p. 808-16.
[5] Galanello, R., et al., Effect of food, type of food, and time of food intake on deferasirox bioavailability: recommendations for an optimal deferasirox administration regimen. J Clin Pharmacol, 2008. 48(4): p. 428-35.
[6] Borella, E., et al., Use of prior knowledge and extrapolation in paediatric drug development: A case study with deferasirox. Eur J Pharm Sci, 2019. 136: p. 104931.
Reference: PAGE () Abstr 9535 [www.page-meeting.org/?abstract=9535]
Poster: Drug/Disease Modelling - Paediatrics