An investigation into paediatric gastrointestinal physiology and its applications in in silico pbpk modelling for age-appropriate formulations

Goelen, Jan ORCID: 0000-0002-6796-3210 (2023). An investigation into paediatric gastrointestinal physiology and its applications in in silico pbpk modelling for age-appropriate formulations. University of Birmingham. Ph.D.

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Abstract

Drug formulations and dosage strengths intended for the adult population may not be appropriate for paediatric patients, due to developmental changes with age. Performing clinical trials in the paediatric population is challenging due to many factors, therefore formulation development for this population relies on predictive tools that simulate in vivo conditions. However, the development of such tools that predict oral drug disposition is hampered by a lack of physiological data describing the gastro-intestinal tract of the paediatric population. Characterising key parameters will progress predictive tools such as physiologically-based pharmacokinetic (PBPK) modelling and improve representability of paediatric subjects. This thesis specifically characterises (i) the abundance and ontogeny of paediatric intestinal drug metabolising enzymes and transporters (DMET) proteins and (ii) the amount of free fluid within the paediatric colon as two currently unknown parameters. Using pinch biopsies from the paediatric duodenum, the abundance of important DMET proteins were quantified via LC-MS/MS. For this, an established nanoflow method was translated to a microflow, and a new stable-isotope-labelled standard developed. The observed abundancies and ontogeny profiles, such as for intestinal CYP3A4, agreed with adult LC-MS/MS-based data, or historic paediatric data obtained via western blotting. The amount and distribution of fluid within the paediatric colon were quantified using magnetic resonance imaging. The paediatric colonic fluid was dissimilar from reported adult values (with 50% of the subjects having <1 mL of fluid), but no correlation with covariates (sex, age, weight) were observed.

These newfound paediatric physiological data were then integrated into PBPK models. Adapting the default ontogeny profile of intestinal CYP3A4 to the novel profile did not result in clinically different disposition of midazolam, confirming the adequacy of the former in current modelling. Integrating the colonic fluid data in a model for an extended-release formulation of quetiapine saw that, when limited amount of fluid in the colon is present (which is the case for half the paediatric population), ineffective absorption and suboptimal antipsychotic treatment might be prevalent.

In conclusion, the abundance of DMET proteins and the amount of fluid were quantified in the paediatric population. These newly generated data can now be used in predictive tools, with the aim to make formulations for the paediatric population more age-appropriate.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID Horniblow, Richard UNSPECIFIED orcid.org/0000-0002-3996-9236 Brown, Geoffrey UNSPECIFIED UNSPECIFIED Pawar, Gopal UNSPECIFIED UNSPECIFIED Batchelor, Hannah UNSPECIFIED orcid.org/0000-0002-8729-9951
Licence:	All rights reserved
College/Faculty:	Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department:	School of Pharmacy
Funders:	Other
Subjects:	Q Science > QP Physiology R Medicine > RJ Pediatrics R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica
URI:	http://etheses.bham.ac.uk/id/eprint/13796

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