Challenges and Opportunities for Increasing the Knowledge Base Related to Drug Biotransformation and Pharmacokinetics during Growth and Development.
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.
Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospitals and Clinics, University of Missouri-Kansas City, Kansas City, Missouri (J.S.L.); and Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee (B.M.) sleeder@cmh.edu.
J Steven
JS
Leeder
Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospitals and Clinics, University of Missouri-Kansas City, Kansas City, Missouri (J.S.L.); and Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee (B.M.).
Bernd
B
Meibohm
D000293:Adolescent; D041923:Adolescent Development; D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D002648:Child; D002657:Child Development; D002675:Child, Preschool; D003198:Computer Simulation; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051188:Knowledge Bases; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics
D004798:Enzymes; D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations