PREDICTING PHARMACOKINETIC BEHAVIOR AND DOSE OF SILDENAFIL AND VORICONAZOLE IN NEONATAL AND PEDIATRIC POPULATIONS BY IN VITRO METABOLISM AND PBPK MODELING

Zane, Nicole

PREDICTING PHARMACOKINETIC BEHAVIOR AND DOSE OF SILDENAFIL AND VORICONAZOLE IN NEONATAL AND PEDIATRIC POPULATIONS BY IN VITRO METABOLISM AND PBPK MODELING

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March 19, 2019

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Zane, Nicole
- Affiliation: Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics

Abstract

Quantitative and qualitative differences in drug metabolizing enzymes (DMEs) from birth to adulthood affect drug clearance. Yet the effect of these differences on pediatric drug disposition is poorly understood. Moreover, drug disposition relies on both metabolic clearance and age-dependent differences in physiology. The overall goal of this dissertation was to develop a bottom-up experimental and modeling approach to predict pharmacokinetics (PK) of drugs in pediatric populations. Voriconazole and sildenafil were selected because they are (i) cleared predominantly by oxidative metabolism and (ii) administered to children and premature neonates, respectively. Hepatic intrinsic clearance from adult and pediatric tissues was elucidated and then incorporated into a physiologically based pharmacokinetic (PBPK) model to predict PK for each drug. The voriconazole model retrospectively validated this approach by comparing the model's output against the abundant pediatric clinical data. It showed that the drug was cleared approximately 3-fold faster and bioavailability was nearly half in children ages 2-10 years compared to adults due to contribution differences in CYP2C19 and CYP3A4. Quantitative proteomic analysis of hepatic tissues revealed higher expression of CYP2C19 protein and higher catalytic efficiency in children compared to adults. Sildenafil metabolism studies demonstrated the predominant enzymes are CYP3A5 and either CYP3A4 or CYP3A7, which refutes previous reports identifying CYP3A4 and CYP2C9. Furthermore, these studies revealed that CYP3A7 is a steroid-specific enzyme that generates a unique testosterone metabolite. The expression and functional activity of the three CYP3A isoforms in fetal, pediatric, and adult hepatic tissues was elucidated. This data along with hepatic in vitro sildenafil metabolism was incorporated into a prospective PBPK model for premature neonates. The model revealed how ontogeny affects sildenafil clearance in premature neonates. It also predicted the influence of physiological factors and the potential effect of drug-drug interactions (DDI) on sildenafil PK. The key outcome was the development of a bottom-up PBPK model in pediatric populations by adapting a validated adult model, which was based on hepatic in vitro metabolism studies and expression of relevant enzymes from hepatic tissue incorporated with physiologic parameters. This innovative approach can be adapted to predict disposition and clinically significant DDI without relying solely on clinical trials.

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