Drug Metabolism and Interactions in Pediatric Patients

Abstract

Infants and children are different from adults, also in the way they handle (pharmacokinetics, PK) and subsequently respond (pharmacodynamics) to drugs. Developmental PK focuses on developmental aspects of absorption, distribution, metabolism and excretion of drugs, subsequent potentially affecting drug pharmacological response, and safety. All drug metabolism‐mediated phase I and II reactions display isoenzyme specific age‐dependent activity, that is, ontogeny. Several in vitro and clinical studies of probe drugs used in children revealed that ontogeny in drug‐metabolizing enzymes and transporters results in significant differences in PK, safety, and interactions of drugs between children and adults. Altered drug metabolism and/or transporters can lead to the development of adverse effects in infants or, reversely, may result in relative tolerance in this population compared to adulthood because of insufficient toxic metabolite formation. Age‐dependent changes in liver drug metabolism have been most extensively studied. In addition to the maturation of drug‐metabolizing enzyme activities, age‐dependent changes in (i) uptake and efflux drug transporters; (ii) extent of plasma protein binding; (iii) liver size relative to body weight (BW); (iv) liver blood flow; and (v) microgram microsomal protein per gram liver are the key factors that influence the changes in drug metabolism and its hepatic clearance in pediatric populations compared with adults. In this chapter, drug metabolism in pediatric patients and the factors that mediate the variability in relation to phase I and II enzymes is described. The impact of accurate evaluation of drug metabolism on drug clearance and dose determination in pediatric patients are briefly discussed; deficient in clinical studies and dose selection in relation to off‐label drug therapy in pediatric populations are also discussed. Furthermore, the information that described the metabolism‐mediated drug interaction or adverse drug reactions (ADRs) is then reviewed. Finally, tools to study the drug metabolism in this populations and overseen limitation are summarized.