Formulation performance in paediatric patients - in vitro predictive models and biowaivers

  • Joana Martir

Student thesis: Doctoral ThesisPhD


The field of paediatric biopharmaceutics is currently evolving, as a result of the distinct needs of this population regarding formulation design and performance. Age-appropriate biopharmaceutical tools for paediatric formulation development are warranted due to their potential in minimising scientific and regulatory risks.
The aim of this thesis was to develop in vitro predictive tools to aid understanding of formulation performance in paediatrics, with emphasis on co-administration of medicines with food and drinks (vehicles), and to explore the extension of the Biopharmaceutics Classification System (BCS) to paediatrics. Common practices of medicine co-administration with vehicles were investigated and compared with the relevant guidelines. The possible negative outcomes of this practice were highlighted, revealing the need for a unified mandatory guidance on administration practices, vehicle selection and assessment. Frequently recommended vehicles were selected, and their physicochemical properties and composition were characterised. These differences had an impact on the solubility of two poorly soluble drugs, montelukast and mesalazine. Age-appropriate in vitro dissolution testing was developed to predict the impact of medicine co-administration on drug product performance. Drug dissolution was affected by co-administration with food and drinks in comparison to direct administration of formulation, and the time between preparation and testing of the drug-vehicle mixture. A biorelevant dissolution testing setup was developed, which predicted the in vivo formulation performance after medicine co-administration with vehicles in infants. Ultimately, the potential of dissolution studies with mini-paddle in mimicking paediatric administration practices and predicting in vivo drug performance was shown. An extension of current BCS-based biowaiver criteria into paediatrics was explored but shown not to be feasible due to gaps in knowledge regarding the gastrointestinal tract of paediatric patients, which hinder the development of a paediatric-BCS.
Overall, this thesis provides a useful insight on the critical aspects of paediatric biopharmaceutics, with an overview on the possible impact of administration practices on paediatric clinical outcomes. This could be a starting point towards developing physiologically relevant in vitro biopharmaceutical tools, which can be used to assess product drug performance in paediatric subpopulations.
Date of Award4 Sept 2019
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorNikoletta Fotaki (Supervisor) & Stephen Husbands (Supervisor)

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