Population pharmacokinetics and dosing recommendations for the use of deferiprone in children younger than 6 years of age

Leiden Academic Centre for Drug Research, Leiden, The Netherlands; Pediatric Hematology Unit - Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Italy; Azienda Ospedaliera di Padova, Italy; Azienda Ospedaliera Ospedali Riuniti Villa Sofia - Cervello, Palermo, Italy; Azienda Ospedaliera Antonio Cardarelli, Napoli, Italy; Clinica Pediatrica Universita di Sassari - ASL1, Sassari, Italy; Consorzio per Valutazioni Biologiche e Farmacologiche, Pavia, Italy; ApoPharma Inc., Toronto, Ontario, Canada; Consorzio per Valutazioni Biologiche e Farmacologiche, Pavia, Italy; Clinical Pharmacology & Therapeutics, University College London, United Kingdom.

British Journal of Clinical Pharmacology. 2016;83((3):):593-602
AIMS: Despite long clinical experience with deferiprone, there is limited information on its pharmacokinetics in children < 6 years of age. Here we assess the impact of developmental growth on the pharmacokinetics of deferiprone in this population using a population approach. Based on pharmacokinetic bridging concepts, we also evaluate whether the recommended doses yield appropriate systemic exposure in this group of patients. METHODS Data from a study in which 18 paediatric patients were enrolled were available for the purposes of this analysis. Patients were randomised to three deferiprone dose levels (8.3, 16.7 and 33.3 mg/kg). Blood samples were collected according to an optimised sampling scheme in which each patient contributed to a maximum of five samples. A population pharmacokinetic model was developed using NONMEM v.7.2. Model selection criteria were based on graphical and statistical summaries. RESULTS A one-compartment model with first-order absorption and first-order elimination best described the pharmacokinetics of deferiprone. Drug disposition parameters were affected by body weight, with both clearance and volume increasing allometrically with size. Simulation scenarios show that comparable systemic exposure (AUC) is achieved in children and adults after similar dose levels in mg/kg, with median (5-95th quantiles) AUC values respectively of 340.6 (223.2-520.0) and 318.5 (200.4-499.0) micromol/L*h at 75 mg/kg/day and 453.7 (297.3-693.0) and 424.2 (266.9-664.0) at 100 mg/kg/day t.i.d. doses. CONCLUSIONS Based on the current findings, a dosing regimen of 25 mg/kg t.i.d. is recommended in children below 6 years of age, with the possibility of titration up to 33.3 mg/kg t.i.d.
Study details
Language : English
Credits : Bibliographic data from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine