Pediatric Physiologically Based Pharmacokinetic Model Development: Current Status and Challenges

Abstract

This article provides a brief overview of the development of pediatric physiologically based pharmacokinetic (PPBPK) models, the challenges of uncertain systems information, and finally performance verification considering recent regulatory guidance. Pediatric PBPK (PPBPK) model can incorporate varied manifolds of drug and developmental system information to predict drug PK in children. Health authorities have been receiving a growing number of drug submissions that have used PPBPK. According to a recent review of the FDA office of Clinical Pharmacology, PPBPK modeling has been readily applied for dose regimen selection in a variety of pediatric patient groups via a “learn and confirm” approach. Before applying to pediatrics, a PBPK model is developed using physicochemical, biopharmaceutical, and metabolic parameters of drug and then verified by pharmacokinetics (PK) data in adults. Once the drug parameters are optimized, they can be used in the PPBPK model which contains the ‘systemic’ data of physiology and biochemistry in children. The drug absorption, distribution, metabolism, and excretion (ADME) parameters can be estimated according to developmental changes in physiology and biochemistry in various age groups of children. The model is then applied to simulate the exposure in children. The current challenge is the paucity of available pediatric systems information and oral biopharmaceutics. They are essential to verify PPBPK models and predict PK particularly in neonates and young infants. The recent research on intestinal and hepatic transporter ontogeny, via mRNA and proteomic data, gives us increased understanding of pediatric drug absorption, hepatic uptake, and biliary excretion. Nevertheless, more validated developmental ‘system’ data is needed in this field. Another gap is the lack of good quality pediatric drug studies performed across the age range, which currently is a limitation to the performance verification of PPBPK models. PPBPK models have already improved the pediatric drug development process but the important challenges lie ahead. Further development and verification are constantly required. It may be possible to minimize the number of pediatric subjects used in PK studies and avoid some studies altogether.