Developing in vitro and in silico approaches to predict clinical outcomes: focus on paediatrics

Student thesis: Doctoral ThesisPhD

Abstract

The paediatric gastrointestinal (GI) tract undergoes numerous morphological and physiological changes throughout childhood. Feeding frequency and meals evolve during the first years after birth. These age-related changes have the potential to affect oral drug absorption. The adequacy of using adult in vitro biopharmaceutical tools in paediatrics is uncertain. This thesis aimed to develop in vitro and in silico tools to predict formulation performance in paediatrics. Drug solubility measurements were performed in adult and paediatric biorelevant media. Multivariate analysis of solubility differences between adults and paediatrics revealed that drug solubilisation was related to compound properties (i.e. logP and ionisation), and biorelevant media composition (such as the concentration of bile salts, osmolality, etc.). Age-appropriate in vitro dissolution studies and Physiologically Based Pharmacokinetic (PBPK) models were developed for two model compounds - montelukast and azithromycin. The dissolution of montelukast oral granules and chewable tablets was affected by in vitro hydrodynamics, gastric/intestinal conditions of the GI tract, prandial state, and medicine co-administration practices. Age-related dissolution of montelukast granules predicted the in vivo effect of drug co-administration with dosing vehicles in infants. The integration of µDISS profiler™ dissolution data into the montelukast PBPK model predicted the fasted state exposure of montelukast chewable tablets in adults and children. Integration of montelukast dissolution profiles (USP 4 apparatus) simulating infant fed GI conditions and in vivo co-administration practices into a fed state PBPK model predicted the in vivo drug performance in infants. Azithromycin’s (immediate-release powder for suspension) PBPK model for adults and paediatrics (with age-appropriate in vitro data) revealed that permeation through the gut wall is the key driver of azithromycin oral absorption in both populations, and no alterations of the rate-limiting steps of absorption between adults and paediatrics are expected. The considerations required for the development of predictive age-appropriate in vitro and in silico tools are illustrated in this thesis. The tools developed can be used to investigate the risk of altered oral drug performance in paediatrics.
Date of Award26 May 2021
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorNikoletta Fotaki (Supervisor) & Stephen Husbands (Supervisor)

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