Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters

Abstract

Developmental changes in the biological processes involved in the disposition of drugs, such as membrane transporter expression and activity, may alter the drug exposure and clearance in pediatric patients. Physiologically based pharmacokinetic (PBPK) models take these age‐dependent changes into account and may be used to predict drug exposure in children. As a result, this mechanistic‐based tool has increasingly been applied to improve pediatric drug development. Under the Prescription Drug User Fee Act VI, the US Food and Drug Administration has committed to facilitate the advancement of PBPK modeling in the drug application review process. Yet, significant knowledge gaps on developmental biology still exist, which must be addressed to increase the confidence of prediction. Recently, more data on ontogeny of transporters have emerged and supplied a missing piece of the puzzle. This article highlights the recent findings on the ontogeny of transporters specifically in the intestine, liver, and kidney. It also provides a case study that illustrates the utility of incorporating this information in predicting drug exposure in children using a PBPK approach. Collaborative work has greatly improved the understanding of the interplay between developmental physiology and drug disposition. Such efforts will continue to be needed to address the remaining knowledge gaps to enhance the application of PBPK modeling in drug development for children.

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.…”

Progress in Drug Development–Pediatric Dose Selection: Workshop Summary

“…The gastric fluid composition (bile salts, osmolarity, pH) displays age‐dependent changes, further affected by feeding frequency and type 24 . Drug metabolism and drug transport are additional processes that are sensitive to maturational effects in pediatric patients 25,26 …”

Implementation of a Physiologically Based Pharmacokinetic Modeling Approach to Guide Optimal Dosing Regimens for Imatinib and Potential Drug Interactions in Paediatrics

“…Given the importance of ABCB1 and ABCG2 transporters on biliary excretion of imatinib (Barratt and Somogyi, 2017), the maturation rates of these drug transporters need to be considered. The expression of hepatic and intestinal ABCG2 transporter was not affected by age (Prasad et al, 2016;Cheung et al, 2019), while there are conflicting data on developmental changes in protein expression of hepatobiliary ABCB1 transporter (Mooij et al, 2014;Prasad et al, 2016). However, the clinical pharmacokinetic data and PBPK simulations of digoxin, a probe drug for ABCB1, suggest a rapid maturation and attainment of adult levels of expression within first few months after birth .…”