Francesco Bellanti1, Giovanni C Del Vecchio2, Maria C Putti3, Aurelio Maggio4, Aldo Filosa5, Carlo Cosmi6, Laura Mangiarini7, Michael Spino8, John Connelly8, Adriana Ceci7, Oscar Della Pasqua1,9. 1. Leiden Academic Centre for Drug Research, Leiden, The Netherlands. 2. Paediatric Hematology Unit, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Italy. 3. Azienda Ospedaliera di Padova, Italy. 4. Azienda Ospedaliera Ospedali Riuniti Villa Sofia - Cervello, Palermo, Italy. 5. Azienda Ospedaliera Antonio Cardarelli, Naples, Italy. 6. Clinica Pediatrica Università di Sassari - ASL1, Sassari, Italy. 7. Consorzio per Valutazioni Biologiche e Farmacologiche, Pavia, Italy. 8. ApoPharma Inc., Toronto, Ontario, Canada. 9. Clinical Pharmacology & Therapeutics, University College London, UK.
Abstract
AIMS: 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. 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-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. 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-1 , with median (5-95th quantiles) AUC values, respectively, of 340.6 (223.2-520.0) μmol l-1 h and 318.5 (200.4-499.0) μmol l-1 h at 75 mg kg-1 day-1 , and 453.7 (297.3-693.0) μmol l-1 h and 424.2 (266.9-664.0) μmol l-1 h at 100 mg kg-1 day-1 given as three times daily (t.i.d.) doses. CONCLUSIONS: Based on the current findings, a dosing regimen of 25 mg kg-1 t.i.d. is recommended in children aged <6 years, with the possibility of titration up to 33.3 mg kg-1 t.i.d.
RCT Entities:
AIMS: 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. 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-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. 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-1 , with median (5-95th quantiles) AUC values, respectively, of 340.6 (223.2-520.0) μmol l-1 h and 318.5 (200.4-499.0) μmol l-1 h at 75 mg kg-1 day-1 , and 453.7 (297.3-693.0) μmol l-1 h and 424.2 (266.9-664.0) μmol l-1 h at 100 mg kg-1 day-1 given as three times daily (t.i.d.) doses. CONCLUSIONS: Based on the current findings, a dosing regimen of 25 mg kg-1 t.i.d. is recommended in children aged <6 years, with the possibility of titration up to 33.3 mg kg-1 t.i.d.
Authors: Caterina Borgna-Pignatti; Maria Domenica Cappellini; Piero De Stefano; Giovanni Carlo Del Vecchio; Gian Luca Forni; Maria Rita Gamberini; Roberta Ghilardi; Antonio Piga; Maria Antonietta Romeo; Huaqing Zhao; Avital Cnaan Journal: Blood Date: 2005-12-22 Impact factor: 22.113
Authors: C Borgna-Pignatti; M D Cappellini; P De Stefano; G C Del Vecchio; G L Forni; M R Gamberini; R Ghilardi; R Origa; A Piga; M A Romeo; H Zhao; A Cnaan Journal: Ann N Y Acad Sci Date: 2005 Impact factor: 5.691