Computational Pharmacokinetics During Developmental Windows of Susceptibility

Abstract

Computational modeling has an increasing role in analyses of biological effects, including how the body handles chemicals (i.e., pharmacokinetics or toxicokinetics) and how the body responds to chemicals (i.e., pharmacodynamics or toxicodynamics). Pharmacokinetic models increasingly describe not just adult humans and animals, but also changes with age and life stage (e.g., pregnancy and fetal exposures, lactational exposures, and childhood growth). Physiologically based pharmacokinetic models provide an important route to estimate the potential changes in internal dose that may occur throughout the life cycle. These models require inputs describing changes in physiology, metabolism, and exposure with age and life stage. A particular challenge exists when the “equivalent” developmental period in the rodents and humans differs (e.g., early postnatal in rats and in utero in humans) such that the “equivalent” window of susceptibility to toxic effects of the chemical may involve substantially different exposures (e.g., lactational versus placental transfer). Pharmacodynamic modeling could similarly address changes with age, but few such models currently exist. The growth of systems biology is anticipated to change this over the coming decade.

Acknowledgments

The helpful comments of Drs. Chris Lau, Elaine Cohen-Hubal, and Linda S. Birnbaum are acknowledged. This article has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the view of the agency.