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PEDIATRICS Vol. 113 No. 4 April 2004, pp. 973-983

SUPPLEMENT ARTICLE

Pediatric Pharmacokinetic Data: Implications for Environmental Risk Assessment for Children

Gary Ginsberg, PhD*, Dale Hattis, PhD{ddagger}, Richard Miller, PhD§ and Babasaheb Sonawane, PhD||

* Connecticut Department of Public Health, Hartford, Connecticut
{ddagger} Clark University, Center for Technology, Environment & Development, Worcester, Massachusetts
§ Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, New York
|| National Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, Washington, DC

Pharmacology and toxicology share a common interest in pharmacokinetic data, especially as it is available in pediatric populations. These data have been critical to the clinical pharmacologist for many years in designing age-specific dosing regimens. Now they are being used increasingly by toxicologists to understand the ontogeny of physiologic parameters that may affect the metabolism and clearance of environmental toxicants. This article reviews a wide range of physiologic and metabolic factors that are present in utero and in early postnatal life and that can affect the internal dose of an absorbed chemical and its metabolites. It also presents a child/adult pharmacokinetic database that includes data for 45 therapeutic drugs organized into specific children’s age groupings and clearance pathways. Analysis of these data suggests that substantial child/adult differences in metabolism and clearance are likely for a variety of drugs and environmental chemicals in the early postnatal period. These results are also relevant to in utero exposures, where metabolic systems are even more immature, but exposures are greatly modified by the maternal system and placental metabolism. The implications of these child/adult differences for assessing children’s risks from environmental toxicants is discussed with special focus on physiologically based pharmacokinetic modeling strategies that could simulate children’s abilities to metabolize and eliminate chemicals at various developmental stages.

Key Words: children • metabolism • pharmacokinetics • risk assessment

Abbreviations: PK, pharmacokinetics • TK, toxicokinetics • CYP, cytochrome P-450 • ADR, adverse drug reaction • Vd, volume of distribution • EH, epoxide hydrolase • CBZ, carbamazepine • t1/2, drug half-life • PBTK, physiologically based toxicokinetic • GI, gastrointestinal

Received for publication Oct 7, 2003; Accepted Oct 20, 2003.


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