Potential implications of DMET ontogeny on the disposition of commonly prescribed drugs in neonatal and pediatric intensive care units

Abstract

Introduction: Pediatric patients, especially neonates and infants, are more susceptible to adverse drug events as compared to adults. In particular, immature small molecule drug metabolism and excretion can result in higher incidences of pediatric toxicity than adults if the pediatric dose is not adjusted.Area covered: We reviewed the top 29 small molecule drugs prescribed in neonatal and pediatric intensive care units and compiled the mechanisms of their metabolism and excretion. The ontogeny of Phase I and II drug metabolizing enzymes and transporters (DMETs), particularly relevant to these drugs, are summarized. The potential effects of DMET ontogeny on the metabolism and excretion of the top pediatric drugs were predicted. The current regulatory requirements and recommendations regarding safe and effective use of drugs in children are discussed. A few representative examples of the use of ontogeny-informed physiologically based pharmacokinetic (PBPK) models are highlighted.Expert opinion: Empirical prediction of pediatric drug dosing based on body weight or body-surface area from the adult parameters can be inaccurate because DMETs are not mature in children and the age-dependent maturation of these proteins is different. Ontogeny-informed-PBPK modeling provides a better alternative to predict the pharmacokinetics of drugs in children.

Keywords: Pediatric precision medicine; developmental toxicity; drug metabolism; drug transport; ontogeny; pediatric pharmacology.

Figure 1.

Summary of age-associated changes in absorption, distribution, metabolism, and excretion (ADME) processes from neonates to adults (the artwork was supported by Servier Medical Art, licensed under CC BY 3.0).

Figure 2.

Top drugs in NICU (A) and PICU (B) by number of doses administered from January 2019 to December 2019 at Providence Sacred Heart Medical Center and Children’s Hospital, Spokane, WA, USA.

Figure 3.

Relative importance of drug elimination mechanisms of top dosed drugs in the NICU/PICU, i.e., (A) prominent route of elimination, (B) prominent excretory pathways of renally eliminated drugs, (C) prominent enzyme families of hepatically eliminated drugs, and (D) prominent enzymes of hepatically eliminated drugs.

Figure 4.

Schematic workflow of DMET ontogeny linked-pediatric PBPK model development for extrapolation of adult data to predict drug disposition in children. The model structure is based on a middle-out approach, where reported clinical pharmacokinetic (PK) data and in-house experimental data can be used as input parameters (i.e., system- and drug-specific parameters). DMET proteins ontogeny data are crucial for pediatric model development. SAD: single ascending dose, MAD: multiple ascending doses.