Performance Evaluation of Montelukast Pediatric Formulations: Part II \u2014 a PBPK Modelling Approach

Mariana Guimarães,Maria Vertzoni,Nikoletta Fotaki

doi:10.1208/s12248-021-00662-1

Abstract

This study aimed to build a physiologically based pharmacokinetic (PBPK) model coupled with age-appropriate in vitro dissolution data to describe drug performance in adults and pediatric patients. Montelukast sodium was chosen as a model drug. Two case studies were investigated: case study 1 focused on the description of formulation performance from adults to children; case study 2 focused on the description of the impact of medicine co-administration with vehicles on drug exposure in infants. The PBPK model for adults and pediatric patients was developed in Simcyp® v18.2 informed by age-appropriate in vitro dissolution results obtained in a previous study. Oral administration of montelukast was simulated with the ADAM™ model. For case study 1, the developed PBPK model accurately described montelukast exposure in adults and children populations after the administration of montelukast chewable tablets. Two-stage dissolution testing in simulated fasted gastric to intestinal conditions resulted in the best description of in vivo drug performance in adults and children. For case study 2, a good description of in vivo drug performance in infants after medicine co-administration with vehicles was achieved by incorporating in vitro drug dissolution (under simulated fasted gastric to fed intestinal conditions) into a fed state PBPK model with consideration of the in vivo dosing conditions (mixing of formulation with applesauce or formula). The case studies presented demonstrate how a PBPK absorption modelling strategy can facilitate the description of drug performance in the pediatric population to support decision-making and biopharmaceutics understanding during pediatric drug development.Graphical abstract

Highlights

The relevance of physiologically based pharmacokinetic (PBPK) modelling for biopharmaceutic applications in adults is a growing field, as recognised by a recent FDA draft guidance [1]
Further complications in the pediatric population arise as a result of the lack of formulations designed for the target pediatric population, which lead to drug manipulation practices [14–16], such as tablet splitting and crushing, and/or drug products being mixed with small amounts of food or drink vehicles to facilitate administration [14–16]
This study aims to demonstrate the potential applications of a PBPK absorption modelling strategy coupled with biorelevant in vitro dissolution testing for evaluating drug product performance in pediatric patients

Summary

Introduction

The relevance of physiologically based pharmacokinetic (PBPK) modelling for biopharmaceutic applications in adults is a growing field, as recognised by a recent FDA draft guidance [1]. PBPK modelling can be applied in all stages of adult drug development. The pediatric drug development process should start during the early stages of the adult drug development programme [7]. This strategy allows industry sponsors to gather valuable knowledge on adult drug pharmacokinetic (PK) studies, which can later support the description of drug product performance in the pediatric population [11]. Further complications in the pediatric population arise as a result of the lack of formulations designed for the target pediatric population, which lead to drug manipulation practices [14–16], such as tablet splitting and crushing, and/or drug products being mixed with small amounts of food or drink vehicles to facilitate administration [14–16]

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