Physiological Modeling of Age-Specific Changes in the Pharmacokinetics of Organic Chemicals in Children

TLDR

Age‑specific pharmacokinetic differences arise mainly from physiological and biochemical changes, and PBPK models can integrate these factors. The study aimed to compile age‑specific physiological data and embed them in a PBPK model to simulate inhalation pharmacokinetics of furan in children aged 6, 10, and 14. The authors assembled literature‑derived physiological parameters, calculated partition coefficients, and used a PBPK model to simulate continuous inhalation exposure to 1 w g/L furan over 30 h in adults and children aged 6, 10, and 14. Simulations indicate that children have about 1.5‑fold higher steady‑state blood furan concentrations and up to 1.25‑fold higher liver metabolite levels than adults, demonstrating the model’s utility for predicting age‑related internal dose differences.

Abstract

Age-specific changes in the pharmacokinetics of chemicals are primarily due to differences in physiological and biochemical factors. For integrating the available information on the age-dependent changes in the physiological and biochemical factors, and for evaluating their combined influence on the pharmacokinetics of chemicals, physiologically based pharmacokinetic (PBPK) models are potentially useful. The objectives of this study were, therefore, (1) to assemble information on age-specific differences in physiological parameters such as alveolar ventilation rate, cardiac output, tissue volumes, tissue blood flow rates, and tissue composition for children of various age groups, and (2) to incorporate these data within a PBPK model for simulating the inhalation pharmacokinetics of a highly metabolized, volatile organic chemical (furan) in children of specific age groups (6, 10, and 14 yr old). The age-specific data on various physiological parameters were assembled following a review of the relevant literature and the hepatic metabolism rate of furan was set equal to the liver blood flow rate in adults and children. The blood:air and tissue:blood partition coefficients were calculated using molecular structure information along with the data on the blood and tissue composition (lipid and water contents) in children and adults. The PBPK model was used to simulate the pharmacokinetics of furan in adults and children (6, 10, and 14 yr old) exposed continuously for 30 h to 1 w g/L of this chemical in inhaled air. The model simulations suggest that, for the same exposure conditions, the blood concentration of furan is likely to be greater in children by a factor of 1.5 (at steady state) than in adults, and the maximal factor of adult-children differences in liver concentration of furan metabolite is about 1.25. The PBPK model framework developed in this study should be useful for predicting the adult-children differences in internal dose of chemicals for risk assessment applications.