Optimizing pediatric dosing: a developmental pharmacologic approach

Abstract

Many physiologic differences between children and adults can result in age-related differences in pharmacokinetics. Understanding the effects of age on bioavailability, volume of distribution, protein binding, hepatic metabolic isoenzymes, and renal elimination can provide insight into optimizing doses for pediatric patients. We performed a search of English-language literature using the MEDLINE database regarding age and pharmacokinetics (1979-July 2008). We then evaluated the literature with an emphasis on drugs with one primary elimination pathway, such as renal clearance or a pathway involving a single metabolic isoenzyme. Our mechanistic-based analysis revealed that children need weight-corrected doses that are substantially higher than adult doses for drugs that are metabolically eliminated solely by the specific cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2C9, and CYP3A4. In contrast, weight-corrected doses for drugs eliminated by renal excretion or metabolism involving CYP2C19, CYP2D6, N-acetyltransferase 2, or uridine diphosphate glucuronosyltransferases are similar in children and adults. In children, bioavailability of drugs with high first-pass metabolism is decreased for drugs metabolized by CYP1A2, CYP2C9, and CYP3A4. Limited data suggest that by age 5 years, bioavailability of drugs affected by efflux transporters should be equivalent to that of adults. Using a pharmacokinetics-based approach, rational predictions can be made for the effects of age on drugs that undergo similar pathways of elimination, even when specific pharmacokinetic data are limited or unavailable.