Innovative approaches and recent advances in the study of ontogeny of drug metabolism and transport

Abstract

The disposition of a drug is driven by various processes, such as drug metabolism, drug transport, glomerular filtration and body composition. These processes are subject to developmental changes reflecting growth and maturation along the paediatric continuum. However, knowledge gaps exist on these changes and their clinical impact. Filling these gaps may aid better prediction of drug disposition and creation of age-appropriate dosing guidelines. We present innovative approaches to study these developmental changes in relation to drug metabolism and transport. First, analytical methods such as including liquid chromatography-mass spectrometry for proteomic analyses allow quantitation of the expressions of a wide variety of proteins, e.g. membrane transporters, in a small piece of organ tissue. The latter is specifically important for paediatric research, where tissues are scarcely available. Second, innovative study designs using radioactive labelled microtracers allowed study-without risk for the child-of the oral bioavailability of compounds used as markers for certain drug metabolism pathways. Third, the use of modelling and simulation to support dosing recommendations for children is supported by both the European Medicines Agency and the US Food and Drug Administration. This may even do away with the need for a paediatric trial. Physiologically based pharmacokinetics models, which include age-specific physiological information are, therefore, increasingly being used, not only to aid paediatric drug development but also to improve existing drug therapies.

A proof of concept using the Ussing chamber methodology to study pediatric intestinal drug transport and age‐dependent differences in absorption

“…Apparent permeability values obtained can be incorporated in physiologically‐based pharmacokinetic (PBPK) models to improve dosing guidelines for the studied population. Alternative techniques to study pediatric intestinal drug absorption could include patient‐derived organoids or organ‐specific exosomes 38,39 . However, for both models, it is still unknown if they retain their age‐specific properties.…”

“…Alternative techniques to study pediatric intestinal drug absorption could include patient‐derived organoids or organ‐specific exosomes. 38 , 39 However, for both models, it is still unknown if they retain their age‐specific properties. Currently, we are working on the possibility of comparing drug transport and metabolism in intestinal organoids from pediatric and adult patients with results obtained in the Ussing chamber.…”

Pediatric Drug‐Drug Interaction Evaluation: Drug, Patient Population, and Methodological Considerations

“…Various ontogeny equations for enzyme expressions have already been developed, and some of them are already implemented in commercial PBPK software 68–72 . Apart from drug‐metabolizing enzymes, there has also been progress in elucidating the impact of ontogeny in drug transporters that can impact drug disposition 73,74 . Therefore, there is an opportunity to apply PBPK modeling to evaluate both drug‐metabolizing enzyme‐ and transporter‐mediated DDIs in the future.…”

Paediatric and obstetrical pharmacology – Pushing the frontier forward

“…7 These research networks have made impacts not only in clinical outcomes but also in understanding the basic biology of drug disposition and response in children, key findings outlined by the elegant work described by Chapron, van Groen and colleagues on the ontogeny of drug disposition and transporter expression and activity in children. 8,9 This work has in turn informed and enabled the translation of these new insights into better approaches for therapy including the use of pharmacogenomic data to inform effective and safe drug therapy, and a better appreciation of drug transfer into breast milk as described by Barker, Verstegen and colleagues. 10,11 Patient empowerment is increasingly recognized as a key component of successful health care.…”

“…Paediatrics and obstetrics pharmacological research has been greatly facilitated by the development of national and international research networks to address the problem of identifying adequate numbers of children or pregnant women for clinical trials, as described by Turner and colleagues in a European context 7 . These research networks have made impacts not only in clinical outcomes but also in understanding the basic biology of drug disposition and response in children, key findings outlined by the elegant work described by Chapron, van Groen and colleagues on the ontogeny of drug disposition and transporter expression and activity in children 8,9 . This work has in turn informed and enabled the translation of these new insights into better approaches for therapy including the use of pharmacogenomic data to inform effective and safe drug therapy, and a better appreciation of drug transfer into breast milk as described by Barker, Verstegen and colleagues 10,11 …”