Project Details

Age-dependent differences in intestinal metabolism impact pediatric bioavailability of Voriconazole

Nicole Zane, PharmD, PhD

Summary

BACKGROUND: Voriconazole, a potent triazole antifungal, improves survival with less adverse side effects compared to other drugs for the treatment of invasive fungal infections. However, it has hypervariable pharmacokinetics and its clearance in children (2-12 years old) is 3-fold higher and bioavailability is one half of adult values. GAP: An important gap in our knowledge exists that explain the mechanisms that result in higher clearance and lower bioavailability of voriconazole and places children at a substantial risk for sub-therapeutic concentrations and treatment failures. This research will investigate potential differences in intestinal metabolism of voriconazole in children, which can be incorporated into a PBPK model to guide dosing. HYPOTHESIS: 1. Age-dependent changes in the expression/activity of intestinal DMEs play a pivotal role in determining the oral bioavailability and exposure (concentrations) of voriconazole. 2. The oral bioavailability of voriconazole can be predicted in children using a PBPK model. METHODS: Children already receiving oral voriconazole as standard of care will be enrolled in an open label, cross-over clinical trial to monitor plasma voriconazole levels after voriconazole administration with and without grapefruit juice to inhibit intestinal metabolism of voriconazole. RESULTS: Pending. IMPACT: Despite the unpredictable pediatric pharmacokinetics that leads to therapeutic failure, voriconazole is the first-line therapeutic option in children. By elucidating the role of intestinal metabolism to the lower bioavailability of voriconazole, a PBPK model can be developed to determine an optimal dosing regimen for voriconazole. The results of this proposed research will also significantly enhance the understanding of age-dependent intestinal first-pass metabolism differences affecting the pharmacokinetics and, therefore, dose of many orally administered drugs.