title: Population pharmacokinetics and dosing recommendations for the use of deferiprone in children younger than 6 years.
abstract: Despite long clinical experience with deferiprone, there is limited information on its pharmacokinetics in children aged <6 years. 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.
  
  
  
  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-1). 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.
  
  
  
  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-1, with median (5-95thquantiles) AUC values, respectively, of 340.6 (223.2-520.0) μmol l-1h and 318.5 (200.4-499.0) μmol l-1h at 75 mg kg-1day-1, and 453.7 (297.3-693.0) μmol l-1h and 424.2 (266.9-664.0) μmol l-1h at 100 mg kg-1day-1given as three times daily (t.i.d.) doses.
  
  
  
  Based on the current findings, a dosing regimen of 25 mg kg-1t.i.d. is recommended in children aged <6 years, with the possibility of titration up to 33.3 mg kg-1t.i.d.
authors.affiliation: Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bellanti
authors.affiliation: Paediatric Hematology Unit, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Italy.
authors.forename: Giovanni C
authors.initials: GC
authors.lastname: Del Vecchio
authors.affiliation: Azienda Ospedaliera di Padova, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Putti
authors.affiliation: Azienda Ospedaliera Ospedali Riuniti Villa Sofia - Cervello, Palermo, Italy.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Maggio
authors.affiliation: Azienda Ospedaliera Antonio Cardarelli, Naples, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Filosa
authors.affiliation: Clinica Pediatrica Università di Sassari - ASL1, Sassari, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Cosmi
authors.affiliation: Consorzio per Valutazioni Biologiche e Farmacologiche, Pavia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mangiarini
authors.affiliation: ApoPharma Inc., Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Spino
authors.affiliation: ApoPharma Inc., Toronto, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Connelly
authors.affiliation: Consorzio per Valutazioni Biologiche e Farmacologiche, Pavia, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Ceci
authors.affiliation: Leiden Academic Centre for Drug Research, Leiden, The Netherlands.|Clinical Pharmacology & Therapeutics, University College London, UK.
authors.forename: Oscar
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D002675:Child, Preschool; D003198:Computer Simulation; D000077543:Deferiprone; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D007502:Iron Chelating Agents / Q000493:pharmacokinetics; D008297:Male; D008954:Models, Biological; D011728:Pyridones / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D016037:Single-Blind Method
chemical_list: D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone
keywords: deferiprone; dose rationale; paediatrics; pharmacokinetic bridging; thalassaemia