Changes in Individual Drug-independent System Parameters during Virtual Pediatric Pharmacokinetic Trials: Introducing Time-varying Physiology into a Pediatric PBPK Model

Although both POPPK and physiologically based pharmacokinetic (PBPK) models can account for age and other covariates within a pediatric 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 pediatric PBPK model, to allow for continuous updating of anatomical, physiological and biological processes in each individual subject over time. The Simcyp® pediatric PBPK model simulator system parameters were reanalyzed to assess the impact of re-defining the individual over the study period. A schedule for re-defining parameters within the Simcyp® pediatric 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 (<5% change in abundance) with subject maturation. The re-sampling frequency decreased as age increased, reaching biweekly by 6 months of age. The PK of both sildenafil and phenytoin were predicted better at the end of a prolonged study period using the time varying vs fixed PBPK models. Pediatric PBPK models which account for time-varying system parameters during prolonged studies may provide more mechanistic PK predictions in neonates and infants.

Author(s): Khaled Abduljalil, Masoud Jamei, Amin Rostami-Hodjegan, Trevor Johnson

Year: 2014 年 05 月 1 日

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