Mechanisms Underlying Altered Antifungal Drug Disposition in Children

One of the Thakker Lab’s goals is to develop a better understanding of role of drug metabolizing enzymes and transporters in differential drug disposition among pediatric vs. adult populations.  Ongoing research studies are aimed at elucidating the role of drug metabolizing enzymes and transporters in the disposition antifungal drugs to explain their greater clearance in children vs. adults.

Several factors contribute to the differences in the drug disposition often observed between children and adults.  Age related changes in drug metabolizing enzymes, transporters, and protein binding often contribute to altered clearance and therapeutic exposure of drugs in children compared to adults.  Consequently, dose adjustment is often required to achieve safe and adequate exposure.  Our goal is to conduct in vitro metabolism and transport studies of antifungal drugs, voriconazole and micafungin, using hepatic tissue from children and adult to investigate the mechanisms underlying the observed differences in their in vivo disposition.  These retrospective studies will ultimately enable us to predict differences in drug clearance between children and adults.  Voriconazole, whose systemic clearance depends on hepatic metabolism, is cleared 3-fold faster in children vs. adults.  Hepatic microsomes derived from pediatric tissue metabolized voriconazole at a faster rate than that did microsomes form adult liver.  Further studies showed that CYP2C19 and FMO enzymes contributed to most of the difference in metabolic clearance.  Micafungin is eliminated predominantly unchanged in the bile, and is cleared faster in neonates than adults.  In vitro studies suggest that large differences in the free-fraction of micafungin in plasma from neonates vs. adults may contribute the observed differences in clearance between these two populations.