State-of-the-Art Review on Physiologically Based Pharmacokinetic Modeling in Pediatric Drug Development

Abstract

Physiologically based pharmacokinetic modeling and simulation is an important tool for predicting the pharmacokinetics, pharmacodynamics, and safety of drugs in pediatrics. Physiologically based pharmacokinetic modeling is applied in pediatric drug development for first-time-in-pediatric dose selection, simulation-based trial design, correlation with target organ toxicities, risk assessment by investigating possible drug-drug interactions, real-time assessment of pharmacokinetic-safety relationships, and assessment of non-systemic biodistribution targets. This review summarizes the details of a physiologically based pharmacokinetic modeling approach in pediatric drug research, emphasizing reports on pediatric physiologically based pharmacokinetic models of individual drugs. We also compare and contrast the strategies employed by various researchers in pediatric physiologically based pharmacokinetic modeling and provide a comprehensive overview of physiologically based pharmacokinetic modeling strategies and approaches in pediatrics. We discuss the impact of physiologically based pharmacokinetic models on regulatory reviews and product labels in the field of pediatric pharmacotherapy. Additionally, we examine in detail the current limitations and future directions of physiologically based pharmacokinetic modeling in pediatrics with regard to the ability to predict plasma concentrations and pharmacokinetic parameters. Despite the skepticism and concern in the pediatric community about the reliability of physiologically based pharmacokinetic models, there is substantial evidence that pediatric physiologically based pharmacokinetic models have been used successfully to predict differences in pharmacokinetics between adults and children for several drugs. It is obvious that the use of physiologically based pharmacokinetic modeling to support various stages of pediatric drug development is highly attractive and will rapidly increase, provided the robustness and reliability of these techniques are well established.

Characterization of the Ontogeny of Hepatic UDP‐Glucuronosyltransferase Enzymes Based on Glucuronidation Activity Measured in Human Liver Microsomes

“…Pediatric physiologically based pharmacokinetic (PBPK) modeling is a valuable tool to predict the impact of age on the exposure of metabolized drugs. Such models consider age‐dependent changes in physiological parameters including maturation of organ size, function, and composition and can also include nonmonotonic metabolic maturation processes . A recent guidance from the European Medicines Agency advocated the need to address the effects of ontogeny on quantitative changes in the contribution of elimination pathways across pediatric age groups…”

“…Such models consider age-dependent changes in physiological parameters including maturation of organ size, function, and composition and can also include nonmonotonic metabolic maturation processes. [10][11][12][13] A recent guidance from the European Medicines Agency advocated the need to address the effects of ontogeny on quantitative changes in the contribution of elimination pathways across pediatric age groups. 14 To date, the ontogeny of 7 hepatic UGT isoforms (UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15, and UGT2B17) has been evaluated based on glucuronidation activity or protein abundance determined in human liver microsomes (HLMs) in independent studies.…”

A Retrospective Evaluation of Allometry, PopulationPharmacokinetics,andPhysiologically‐Based Pharmacokineticsfor Pediatric Dosing Using Clearance as a Surrogate

“…Several evaluations of the PBPK approach for small molecule drugs are reported in the literature. [15][16][17][18] Johnson et al 15 compared the performance of CL prediction by simple allometry and pediatric PBPK model incorporated in Simcyp (Certara, Sheffield, UK) for 11 drugs and demonstrated better prediction accuracy for PBPK compared with simple allometry, especially in children < 2 years old. Zhou et al 17 used 10 compounds metabolized by Cytochrome P450 (CYP)3A4 to demonstrate the value of PBPK pediatric predictions for children < 2 years of age.…”

“…Several evaluations of the PBPK approach for small molecule drugs are reported in the literature . Johnson et al .…”

Physiologically‐Based Pharmacokinetic Modeling vs. Allometric Scaling for the Prediction of Infliximab Pharmacokinetics in Pediatric Patients

“…PBPK models must first be calibrated, informed, and evaluated with PK data in adults before their predictions can become reliable in the pediatric space. The practice of PBPK modeling to support pediatric clinical trial planning in the context of small molecule drugs has achieved critical mass with regulatory support from both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) . In contrast to allometric models, PBPK models can use physiologic knowledge of growth and maturation to account for the ontogeny of key distribution and clearance processes in young children, even neonates and preterm infants …”