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
• pediatric pharmacology
• developmental toxicity
• drug metabolism
• drug transport
• ontogeny

Article Highlights

1. Pediatric patients, especially neonates and infants, are more susceptible to adverse drug events as compared to adults, in part due to immature drug detoxification mechanisms.

2. Such developmental differences may result in toxicities that would not be observed in adults. This, along with prevalent off-label use of drugs in children without clinical pharmacokinetic data is a critical challenge in pediatric pharmacotherapy. This requires a critical understanding and application of the ontogeny of drug metabolism and excretion in predicting drug dosing for children.

3. Ontogeny-informed physiologically-based pharmacokinetic modeling is an emerging alternative to empirical scaling of drug dosing, which can be considered not only in the first-in-child dosing of new drugs but also to predict the safe and effective dosing of the prescription drugs in neonatal and pediatric intensive care units.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplemental material

Supplemental data for this article can be accessed here.

Additional information

Funding

The work was partially supported by the Department of Pharmaceutical Sciences, WSU, Spokane, WA and NIH/NICHD grant (R01-HD081299).