title: Use of an integrated modelling and simulation approach to develop a simplified peginterferon alfa-2a dosing regimen for children with hepatitis C.
abstract: OBJECTIVE
  The aim of the study was to simplify the dosing regimen of peginterferon alfa-2a in paediatric patients with chronic hepatitis C.
  
  
  METHODS
  A population pharmacokinetic (PK) model was developed using PK data from 14 children aged 2-8 years and 402 adults. Simulations were produced to identify a simplified dosing regimen that would provide exposures similar to those observed in the paediatric clinical trials and in the range known to be safe/efficacious in adults. Model predictions were evaluated against observed adult and paediatric data to reinforce confidence of the proposed dosing regimen.
  
  
  RESULTS
  The final model was a two compartment model with a zero order resorption process. Covariates included a linear influence of body surface area (BSA) on apparent oral clearance (CL/F) and a linear influence of body weight on apparent volume of distribution of the central compartment (V1 /F). A simplified dosing regimen was developed which is expected to provide exposures in children aged ≥5 years similar to the dosing formula used in the paediatric clinical trial and within the range that is safe/efficacious in adults. This simplified regimen is approved in the EU and in other countries for the treatment of chronic hepatitis C in treatment-naive children/adolescents aged ≥5 years in combination with ribavirin.
  
  
  CONCLUSIONS
  Pre-existing adult PK data were combined with relatively limited paediatric PK data to develop a PK model able to predict exposure in both populations adequately. This provided increased confidence in characterizing PK in children and helped in the development of a simplified dosing regimen of peginterferon alfa-2a in paediatric patients.
authors.affiliation: Hoffmann-La Roche Inc., Nutley, NJ, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brennan
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lemenuel-Diot
authors.affiliation: SGS Exprimo NV, Mechelen, Belgium and.
authors.forename: Eric
authors.initials: E
authors.lastname: Snoeck
authors.affiliation: Roche Products Ltd, Welwyn, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: McKenna
authors.affiliation: Hoffmann-La Roche Inc., Nutley, NJ, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Solsky
authors.affiliation: Roche Products Ltd, Welwyn, UK.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wat
authors.affiliation: Hoffmann-La Roche Inc., Nutley, NJ, USA.
authors.forename: Navita L
authors.initials: NL
authors.lastname: Mallalieu
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001830:Body Surface Area; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008954:Models, Biological; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a
keywords: chronic hepatitis C; modelling and simulation; paediatric dosing regimen; pegIFN alfa-2a; pharmacokinetics