Challenges and Opportunities for Increasing the Knowledge Base Related to Drug Biotransformation and Pharmacokinetics during Growth and Development

Abstract

It is generally acknowledged that there is a need and role for informative pharmacokinetic models to improve predictions and simulation as well as individualization of drug therapy in pediatric populations of different ages and developmental stages. This special issue contains more than 20 papers responding to the challenge of providing new information on scaling factors, ontogeny functions for drug metabolizing enzymes and transporters, the mechanisms underlying the observed developmental trajectories for these gene products, age-dependent changes in physiologic processes affecting drug disposition in children, as well as in vitro and in vivo studies describing the relative contribution of ontogeny and genetic factors as sources of variability in drug disposition in children. Considered together, these contributions serve to illustrate some of the current limitations regarding sample availability, number, and quality, but also provide a framework that allows for the potential value of the results of a given study to be interpreted within the context of these limitations. Among the challenges for the future are improving our understanding of the mechanisms regulating age-dependent changes in factors influencing drug disposition and response, thereby facilitating generalization to systems lacking detailed data, better integrating age-dependent changes in pharmacokinetics with age-dependent changes in pharmacodynamics, and allowing better predictability and individualization of drug disposition and response across the pediatric age spectrum.

Quantitative mass spectrometry-based proteomics in the era of model-informed drug development: Applications in translational pharmacology and recommendations for best practice

“…abundance is relatively high in fetal and neonatal samples, decreasing rapidly toward adult equivalent levels within 1 year (Leeder & Meibohm, 2016;Mehrotra et al, 2015).…”

Considerations for Implementing Precision Therapeutics for Children

“…Implementation of effective treatment also has the potential to reduce the burden of adverse drug reactions in childhood (e.g., ototoxicity or nephrotoxicity due to aminoglycosides; cardiotoxicity from anthracyclines), consequences that will be borne by the child/family throughout the remainder of the child's life. In children, the process of growth and development, or ontogeny, is now recognized as an important factor influencing drug disposition, and knowledge of the developmental changes in multiple drug biotransformation enzymes and transporters involved in drug absorption, distribution, metabolism, and excretion continues to increase, although it is increasingly apparent that comparable data regarding the ontogeny of transporters are equally important . Additionally, exogenous factors like diet (breast feeding vs. formula feeding) need to be considered for the influence they can have on the ontogeny of drug biotransformation pathways or on the pathways themselves .…”

Ontogeny Related Changes in the Pediatric Liver Metabolome

“…Using an untargeted mass-spectroscopy based metabolomics analysis; we assessed hundreds of metabolites in a set of pediatric liver samples, with both technical and biological validation built into the study design ( Figure 1A). A major challenge for investigations like the one we have conducted is access to a large number of tissue samples of sufficiently high quality to obtain interpretable results; differences in retrieval and preservation methods across various publicly funded and commercial providers has considerable potential to not only contribute to variability in sample quality (16), but may also confound data interpretation. For example, in the United States, availability of tissue samples from infants <1 year of age is relatively infrequent, and those that are available for research tend to be procured from the NIH-funded University of Maryland Brain and Tissue Bank for Developmental Disorders.…”