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Use of an integrated modelling and simulation approach to develop a simplified peginterferon alfa‐2a dosing regimen for children with hepatitis C
Author(s) -
Brennan Barbara J.,
LemenuelDiot Annabelle,
Snoeck Eric,
McKenna Michael,
Solsky Jonathan,
Wat Cynthia,
Mallalieu Navita L.
Publication year - 2016
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12816
Subject(s) - dosing , regimen , medicine , population , pharmacokinetics , ribavirin , body surface area , confidence interval , volume of distribution , pediatrics , chronic hepatitis , immunology , virus , environmental health
Aim 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 ( V 1 / 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. Conclusion 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.