Voriconazole, a potent triazole antifungal used for life-threatening infections, is extensively metabolized by the liver. It displays non-linear pharmacokinetics (PK) in adults but not in children, over a narrow dose range of 3-5 mg/kg. Unexpectedly, voriconazole clearance in children aged 2-10 years is 3-fold higher, requiring an adjustment to a higher weight-normalized dose in pediatric patients. Despite higher starting doses, the variability in voriconazole PK leads to therapeutic failure in some children. Recent studies in the Thakker laboratory have shown that the higher clearance of voriconazole in children can be explained by a higher rate of oxidative metabolism in children compared to adults. It was also revealed that cytochrome (CYP) 3A4, CYP2C19 and flavin-containing mono-oxygenase 3 (FMO) contribute 50, 35 and 15% in adults, respectively, versus 20, 50 and 30% in children, demonstrating a difference in enzyme contribution to voriconazole metabolism. However, investigating the contributions of the ontogeny of drug metabolizing enzymes (DMEs) to the PK of drugs in children is challenging due to ethical concerns regarding pediatric patient recruitment in clinical trials. The central hypothesis of the proposed research is that (i) age-dependent changes in the gene expression profile of CYP and FMO enzymes play a pivotal role in determining the clearance and exposure of voriconazole in the pediatric population;(ii) clearance and bioavailability of drugs metabolized extensively by oxidative enzymes can be predicted in children using a PBPK model based on relevant in vitro metabolism data.
AIM 1. Determine the intrinsic metabolism and specific contributions of CYP3A, CYP2C19, and FMO toward voriconazole metabolism in intestinal tissue in comparison to the hepatic tissue.
AIM 2. Determine the expression and genetic polymorphisms of oxidative enzymes making major contribution to voriconazole metabolism in order to elucidate the effect of genetic variability on its disposition in the pediatric population.
AIM 3. Develop a PBPK model using in vitro data from Aims 1 and 2 to describe the PK behavior of voriconazole in children aged 2-10 years and predict the effect of genetic variability of DMEs on exposure to voriconazole in the pediatric population. The overall goal is to develop experimental and modeling approaches to predict PK in pediatric population for the purpose of developing safe and effective dosing regimens in children with life-threatening diseases. This approach will involve relating clinical PK behavior i adults of metabolically cleared drugs to their in vitro metabolism by enzymes in adult and pediatric tissues, and developing a PBPK model based on in vitro data to predict PK in target pediatric populations.
Knowledge gained from this research can be applied to pediatric clinical trials, which regularly fail due to a lack of understanding of developmental pharmacology. Improving understanding of age-dependent pharmacology will assist in conducting better clinical trials by enabling the selection of optimal doses, thereby recruiting fewer subjects and ensuring a lower failure rate in highly vulnerable pediatric populations.