Pediatric Ontogeny: Moving From Translational Science to Drug Development

In any new science the pioneers focus on the most important and impactful studies in their initial work. This fact leads us to examine the early published studies of Sumner J. Yaffe, MD, a recognized pioneer in pediatric clinical pharmacology. An early hint about Yaffe's approach comes from a 1964 article in which he explores sulfate metabolism during mammalian development,1 and from a 1966 New England Journal of Medicine article about glucuronide-conjugating capacity in infants.2 By 1970, Yaffe had teamed up with the founders of pharmacokinetics, Drs Gerhard Levy and William Jusko, and was incorporating this new quantitative science into his studies of pediatric ontogeny through the use of drugs as pharmacological probes in neonates.3 By 1973, Yaffe was writing about pharmacokinetics and drug disposition in the fetus and newborn infant, and the marriage between pediatric clinical pharmacology and pharmacokinetics was canonized. But for Sumner Yaffe, the scientist, this approach was just a means to understand pediatric ontogeny. The number of studies specifically looking at pediatric ontogeny is very limited. A Medline search from 1946 to the present for "pediatrics" and "ontogeny" finds fewer than 150 articles. If drug development is searched in those articles, only 8 articles can be identified that focus on pediatric ontogeny and drug development. If you take the broader approach and claim that every pharmacokinetic study in pediatric patients provides information on pediatric ontogeny, which is unlikely, then you can add another 4600 studies. You might think that this is discouraging in the face of complex systems of enzymes and transporters, receptors and factors affecting drug elimination, and the changing physiologic systems from the fetus to the adolescent child. In fact, we now have the quantitative tools to piece together information that does inform us about pediatric ontogeny and allow us to use this information to benefit pediatric patients when investigating new drugs. Physiologically based pharmacokinetics (PBPK) is actually an old tool, originally primarily used by toxicologists but now used to develop models that can inform us about pediatric drug disposition in childhood. The modern revival of PBPK in clinical pharmacology in the FDA can be attributed in part to Drs Ping Zhao, formerly of the FDA, and Shiew Mei Huang in the Office of Clinical Pharmacology, who had the foresight to recognize the potential contributions that this quantitative tool could make.4, 5 But investigations of PBPK and issues such as variability in PBPK model parameters were also investigated by FDA scientists such as Dr Jeffrey W. Fisher over 25 years ago.6 Advances in the application of PBPK to understanding pediatric ontogeny and applying these principles to drug development are highlighted in this supplement of The Journal of Clinical Pharmacology. A range of topics are presented that not only encompass major enzymes and transporters in drug disposition but also recognize the most critical periods of drug development such as maternal-fetal drug disposition, which was a focus of Dr Yaffe. Although the natural inclusion of pediatric ontogeny into pediatric clinical pharmacology assessments for new drugs is a major step forward, we need to identify those situations in which our current knowledge is inadequate to verify the predictions of a PBPK model. Those periods of development may include premature infants and drug use in neonates, where the number of drug development and pharmacokinetic studies has been minimal and the risk of the inappropriate application of information from other age groups is considerable.7 Some very thoughtful approaches to incorporating translational science into our understanding of pediatric ontogeny have been conducted. For example, earlier work by investigators associated with this supplement sought to define a method for separating the drug dispositional effects of pharmacogenetics from those related to pediatric ontogeny.8 Similarly, the effects of transporters in pediatric PBPK models have been addressed.9 Therefore, the pediatric clinical and translational science community should renew their efforts to fill in the gaps in knowledge in pediatric ontogeny and drug disposition based on emerging therapies. Some of that information may come from basic science, but critical information will come from well-conducted pharmacokinetic studies just as was done previously by Sumner Yaffe and other pediatric investigators. The other studies that will benefit from advanced pediatric PBPK models in drug development are drug-drug interaction studies and oral absorption studies, both of which are now conducted in adults if a human study is required. Another contribution of translational science to the development of pediatric PBPK models is an increased understanding of changes in physiologic parameters during diseases in pediatric patients. One article in this supplement addresses kidney injury biomarkers in pediatric patients and explores the routes to obtain this critical information if a pediatric physiologic model is to be established. This information has only recently been validated and qualified for drug development in adults, but the same process needs to occur for pediatric patients. In conclusion, pediatric ontogeny is now a critical factor to be incorporated into any pediatric drug development program through the use of model-informed drug development, including PBPK. The steps for applying this knowledge in pediatric drug development are reviewed in this supplement and will become clearer as our experience with these quantitative tools increases. Routine PBPK applications in the future could include pediatric drug-drug interactions and pediatric oral absorption models for new formulations. Additional clinical and translational science studies are necessary both to fill our gaps in knowledge regarding drug dispositional parameters, especially in the developing fetus and neonate, and to build better physiologic disease models for pharmacodynamic biomarkers that can be applied for pediatric use. The outlook for science-based innovation in pediatric drug development is very positive, as has been stated previously.10 The application of PBPK for inclusion of pediatric ontogeny is one of those major science-based innovations. The opinions expressed in this article are those of the authors and should not be interpreted as the position of the US Food and Drug Administration. The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors received no financial support for the research, authorship, and/or publication of this article.