Optimising Drug Dosing Regimens in Paediatric Liver Disease Using Experimentally-Derived Simulation Tools

Abstract

Special and orphan disease populations are at higher risk of adverse drug reactions or ineffective treatment because of the lack of evidence-based recommendations for optimal drug dosing. This is particularly evident in paediatric populations with comorbidities, such as liver disease. Ideally, clinical trials should address these short fallings, however, financial viability, time constraints and ethical considerations hinder studies in these small groups of patients. Whilst precision medicine is not a new concept, the advancement of in silico modelling, for example physiologically based pharmacokinetic (PBPK) models, has provided the necessary tools to inform drug labelling. Nevertheless, in its current form it is not sufficient for stratified dosing unless the systems data required to develop robust PBPK models are obtained for each population. LC-MS/MS based proteomic analysis of 43 control paediatric liver samples (foetal-17 years) and 25 biliary atresia diseased paediatric liver samples (n=14, neonate; n=11, infant) was carried out to establish the absolute abundance of cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes and transporter proteins in relation to adult liver samples.Current PBPK models were used to validate the control paediatric dataset. Although absolute abundance values differed, the abundance relative to adults were consistent across the age ranges. This data emphasised the age-dependent patterns of CYP and UGT maturation, with many enzymes reaching only 20% of adult values in neonates before rapidly increasing to 50-90% of adult values in infants and children (2-11 years). The disparity between paediatric and adult values were further emphasised in diseased paediatric samples. Ontogeny of proteins was delayed in biliary atresia samples, with many proteins expressing 6 to >1000- fold lower compared to age-matched populations. This has the potential to impact the liver’s ability to effectively metabolise many drugs and could result in adverse drug reactions or ineffective treatment, leading to further complications. The data in this study, to our knowledge, is the first comprehensive quantification of relevant drug metabolising enzymes and transporters in biliary atresia. This lays the foundation for the development of in silico populations of paediatric biliary atresia patients to assess optimal drug dosing strategies and inform drug labelling.

Date of Award	31 Dec 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Jill Barber (Supervisor) & Amin Rostami-Hochaghan (Supervisor)