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Impact of Scaling Factor Variation on Pharmacokinetic Outcomes in Pediatric Populations: a Case Study Using Bromodichloromethane (BDCM)
Citation:
Kenyon, E., R. Pegram, J. Lipscomb, AND R. Hines. Impact of Scaling Factor Variation on Pharmacokinetic Outcomes in Pediatric Populations: a Case Study Using Bromodichloromethane (BDCM). FutureTox IV, Crystal City, VA, November 14 - 16, 2018.
Impact/Purpose:
This poster abstract addresses Safe and Sustainable Water Resources on current water systems and regulatory support (SSWR6.01D) with relevance to children’s environmental health. Our studies evaluated the contribution of variability in the maturation of xenobiotic metabolizing enzymes (e.g., CYP2E1), microsomal content and relative liver mass to predicted variability in pharmacokinetic measures in children compared to adults. Measures were estimated using a validated physiologically based pharmacokinetic model for the drinking water disinfection byproduct, BDCM. Our findings indicated that variability in enzyme maturation is reflected in greater variability in predicted pharmacokinetic measures in young children, particularly neonates, compared to adults for all exposure routes and pharmacokinetic outcomes evaluated. Overall these results provide evidence that variability in xenobiotic metabolizing enzyme (XME) maturation can have a large impact on internal dose and potentially risk in pediatric populations.
Description:
In human PBPK models, extrapolating biotransformation rates from in vitro data requires use of scaling factors, including microsomal content (mg of microsomal protein/g liver, MPPGL), enzyme specific content, and liver mass as a fraction of body weight (FVL). We hypothesized that well-known large inter-individual differences in enzyme ontogeny would result in larger variation in pharmacokinetic (PK) outcomes in pediatric populations than those previously observed in adults. We re-parameterized our adult PBPK model for BDCM, a water disinfection byproduct, for pediatric age groups and used Monte Carlo analysis to assess the impact of pediatric scaling factor variation on model-derived PK outcomes compared to adults. BDCM dose metrics were estimated following a single 0.05-L drink or 20-min bath in water containing 5 µg/L BDCM, a typical environmental concentration. MPPGL, CYP2E1 and FVL values reflected the distribution of reported pediatric population values. The impact of scaling factor variability on PK outcome variation was different for each exposure scenario. Higher CYP2E1 expression variability during the neonatal period was reflected in greater variability in predicted PK outcomes, particularly for the oral exposure route. Global sensitivity analysis confirmed the most influential parameter for this variability was CYP2E1. These findings demonstrate the importance of age-dependent scaling factor variability and make a strong case for systematic inclusion of this consideration in risk analysis for pediatric populations. (This abstract does not reflect Agency policy).