Ontogeny of Voriconazole Pharmaockinetics and Metabolism

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DESCRIPTION (provided by applicant): Mortality in children from aspergillosis is more than 50%. Voriconazole is the first-line therapy for this infection, and we have shown a highly significant relationship between voriconazole plasma concentrations and survival. However, voriconazole dosing is currently empirical, and plasma exposure varies between children by 400% or more, even after intravenous dosing. At most, CYP2C19 genotype accounts for 40% of this variability. Therefore it is crucial to quantify the impact of age and illness on the phenotypc activity of CYP2C19, CYP3A4 and flavin mono-oxygenase 3 (FMO3), which together metabolize >90% of voriconazole, and to optimally and rationally dose this critical drug. CYP2C19 and CYP3A4 metabolize nearly half of therapeutic drugs, while the broad substrate specificity of FMO3 suggests its role in pediatric pharmacotherapy has been overlooked, voriconazole serving as a recent example. Therefore, our novel combination of laboratory and statistical methods will set the stage for paradigm-changing methods of pediatric drug development and therapeutic dosing. The hypothesis of our innovative and cross-disciplinary proposal is that the ontogeny of CYP2C19, CYP3A4 and FMO3 will significantly correlate with observed age-related changes in voriconazole PK and will have a major impact on dosing and strategies to most rapidly achieve voriconazole plasma concentrations that are associated with survival. There are three Specific Aims for the project: 1) to characterize the longitudinal CYP2C19, CYP3A4, and FMO3 phenotypes in children and adolescents; 2) to describe voriconazole PK using empirical and physiological models; and 3) to optimize patient voriconazole dosing with model-based Bayesian adaptive control. We will enroll 60 children/adolescents requiring voriconazole in a phase I/II PK study, stratified by age under 2 years (n=10), 2-12 years (n=25) and 12-18 years (n=25). All patients will begin with intravenous (IV) dosing and transition to oral dosing when clinically indicated. From each patient we will collect the following: 1) a blood sample for detection of several CYP2C19 and FMO3 SNPs known to affect enzyme activity; 2) up to 9 steady-state PK blood samples after IV and oral doses; and 3) single PK blood samples 2 hours post-dose at 2 follow-up visits. At the time of the IV voriconazole dose prior to the PK sampling, we will also give single IV microdoses of esomeprazole, midazolam, and ranitidine as a cocktail to probe CYP2C19, CYP3A4, and FOM3 activity, respectively. We will repeat this cocktail with oral doses before the oral PK visit and two follow-up visits. We will estimate DME phenotype using ratios of probe drug metabolite and parent areas under the plasma time concentration curves (AUCs) and simultaneously quantify peripheral blood mononuclear cell DME mRNA and protein. We will test associations between DME phenotype, mRNA, protein, voriconazole PK parameters, age, sex, and degree of illness.