Changes in Individual Drug-Independent System Parameters during Virtual Paediatric Pharmacokinetic Trials: Introducing Time-Varying Physiology into a Paediatric PBPK Model

Although both POPPK and physiologically based pharmacokinetic (PBPK) models can account for age and other covariates within a paediatric population, they generally do not account for real-time growth and maturation of the individuals through the time course of drug exposure; this may be significant...

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Bibliographic Details
Published in:The AAPS journal 2014-05, Vol.16 (3), p.568-576
Main Authors: Abduljalil, Khaled, Jamei, Masoud, Rostami-Hodjegan, Amin, Johnson, Trevor N.
Format: Article
Language:English
Subjects:
Aging - metabolism
Anticonvulsants - pharmacokinetics
Biochemistry
Biomedical and Life Sciences
Biomedicine
Biotechnology
Bronchodilator Agents - pharmacokinetics
Child
Child, Preschool
Clinical Trials as Topic - methods
Humans
Infant
Infant, Newborn
Models, Biological
Pediatrics
Pharmaceutical Preparations - metabolism
Pharmacokinetics
Pharmacology/Toxicology
Pharmacy
Phenytoin - pharmacokinetics
Piperazines - pharmacokinetics
Purines - pharmacokinetics
Reproducibility of Results
Research Article
Sildenafil Citrate
Sulfones - pharmacokinetics
Theophylline - pharmacokinetics
Vasodilator Agents - pharmacokinetics
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Summary:Although both POPPK and physiologically based pharmacokinetic (PBPK) models can account for age and other covariates within a paediatric population, they generally do not account for real-time growth and maturation of the individuals through the time course of drug exposure; this may be significant in prolonged neonatal studies. The major objective of this study was to introduce age progression into a paediatric PBPK model, to allow for continuous updating of anatomical, physiological and biological processes in each individual subject over time. The Simcyp paediatric PBPK model simulator system parameters were reanalysed to assess the impact of re-defining the individual over the study period. A schedule for re-defining parameters within the Simcyp paediatric simulator, for each subject, over a prolonged study period, was devised to allow seamless prediction of pharmacokinetics (PK). The model was applied to predict concentration-time data from multiday studies on sildenafil and phenytoin performed in neonates. Among PBPK system parameters, CYP3A4 abundance was one of the fastest changing covariates and a 1-h re-sampling schedule was needed for babies below age 3.5 days in order to seamlessly predict PK (
ISSN:1550-7416
1550-7416
DOI:10.1208/s12248-014-9592-9