Optimizing Pediatric Dosing: A Developmental Pharmacologic Approach

Gail D. Anderson, Ph.D.; Anne M. Lynn, M.D.

Disclosures

Pharmacotherapy. 2009;29(6):680-690. 

In This Article

Abstract and Introduction

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.

Introduction

Many physiologic differences between children and adults can lead to considerable age-related differences in pharmacokinetics and in optimal drug dosing for the pediatric population. Exponential scaling factors based on size and maturity are often suggested for pediatric dosing.[1–3] Because of their complexity, however, methods derived from these factors are used for only a few drugs. We have come a long way since children were considered "small adults" and since pediatric dosing was thought to involve only correction for body weight. We first appreciated differences in the rates at which hepatic versus renal function mature, and early methods to determine pediatric doses accounted for this. However, a general assumption was that maturation of each of the hepatic pathways progressed at the same rate in children of all ages and adults. Evidence now suggests that age individually affects only the drug metabolic pathways that involve specific cytochrome P450 (CYP) isoenzymes and conjugation isoenzymes.

It would be ideal if pharmacokinetic data were available for all drugs given to neonates, infants, children, and adolescents; however, this is often not the case. Understanding the effects of age on bioavailability, volume of distribution, protein binding, hepatic metabolic isoenzymes, and renal elimination can provide a mechanistic way to initially identify doses for the pediatric population. A similar mechanistic method has been used to predict drug interactions[4–7] and the effect of pregnancy on drug pharmacokinetics[8] when clinical data are limited or unavailable.

The purpose of this review was to provide insight into optimizing dosing for pediatric patients. Thus 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.

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