Recent advances in the ontogeny of drug disposition

Abstract

Developmental changes that occur throughout childhood have long been known to impact drug disposition. However, pharmacokinetic studies in the paediatric population have historically been limited due to ethical concerns arising from incorporating children into clinical trials. As such, much of the early work in the field of developmental pharmacology was reliant on difficult‐to‐interpret in vitro and in vivo animal studies. Over the last 2 decades, our understanding of the mechanistic processes underlying age‐related changes in drug disposition has advanced considerably. Progress has largely been driven by technological advances in mass spectrometry‐based methods for quantifying proteins implicated in drug disposition, and in silico tools that leverage these data to predict age‐related changes in pharmacokinetics. This review summarizes our current understanding of the impact of childhood development on drug disposition, particularly focusing on research of the past 20 years, but also highlighting select examples of earlier foundational research. Equally important to the studies reviewed herein are the areas that we cannot currently describe due to the lack of research evidence; these gaps provide a map of drug disposition pathways for which developmental trends still need to be characterized.

Model‐Based Drug–Drug Interaction Extrapolation Strategy From Adults to Children: Risdiplam in Pediatric Patients With Spinal Muscular Atrophy

“…[15][16][17][18][19] However, wider application of pediatric PBPK modeling in such a context is still lacking. 20,21 The hepatic and intestinal CYP3A ontogeny functions are critical physiological information for the prediction of CYP3A-mediated DDI in children. Several ontogeny models have been proposed based on a combination of surrogate in vitro and in vivo data in children for hepatic CYP3A enzymes, [22][23][24][25][26] namely, Salem et al ("Salem function") 25 and Upreti and Wahlstrom ("Upreti function").…”

“…The mechanistic nature of PBPK modeling enables consideration of age‐dependent differences in physiological parameters 14 and as such has been applied to extrapolate DDI studied in adults to children 15–19 . However, wider application of pediatric PBPK modeling in such a context is still lacking 20,21 . The hepatic and intestinal CYP3A ontogeny functions are critical physiological information for the prediction of CYP3A‐mediated DDI in children.…”

Impact of Inflammation on Cytochromes P450 Activity in Pediatrics: A Systematic Review

“…The maturation and development of organs and enzyme systems influence the pharmacokinetics (PK) and pharmacodynamics of drugs, which may lead to potential variation in the efficacy and safety of drugs [13]. Ontogeny processes are complex and non-linear, making the pediatric population very heterogeneous and as such, the developmental course of all processes contributing to drug disposition cannot be described by a single uniform pattern [14,15]. However, differences in drug-metabolizing enzyme activity appear to be the main determinants of the overall pharmacokinetic differences observed between adults and children [16].…”

“…As with adults, the use of effective and safe therapy in children requires a good understanding of the inter-individual and intra-individual variability due to their growth and maturation, and ontogeny should be taken into account when selecting a drug dosage in children [15,17,20]. Many efforts have been made in recent decades to predict age-related alterations in the PK of drugs in children [14]. Modeling approaches, such as physiology-based PK, The screening of publications was done in several steps.…”

“…Voriconazole is also metabolized by flavin-containing monooxygenase 3, and the contribution of flavin-containing monooxygenase 3 and CYP2C19 has been shown to be five-fold and three-fold higher in children than in adults, respectively [45,103]. It is important to consider these non-CYP phase I drug-metabolizing enzymes because approximatively 25% of metabolically eliminated drugs are first subjected to non-CYP-mediated biotransformation [14]. Moreover, it seems that flavin-containing monooxygenase 3 and CYP2C19 have higher catalytic activity in children than in adults [45,103].…”