PROJECT SUMMARY/ABSTRACT Millions of children throughout the world suffer from neurological diseases, including epilepsy, depression, and infections. Pharmacotherapy is a mainstay of treatment efforts, but optimal dosing is virtually unknown because of the difficulty in measuring drug concentrations in the brain. The extent of brain exposure depends on drug properties and the permeability of the blood brain barrier (BBB). BBB permeability is affected by age and disease and may change over time. In order to adequately characterize exposure, multiple concentration measurements are needed over time. However, serial lumbar punctures in children are rarely advised or indicated. Consequently, the exposure in the brain of most drugs to treat neurological diseases in children is unknown. This lack of data to guide therapy risks toxicity and treatment failure in children. We have developed an approach that combines sophisticated pharmacokinetic modeling with opportunistic, non-invasive, serial drug concentration measurements in the cerebrospinal fluid (CSF) to determine optimal dosing. The work of this proposal will provide a platform to optimize dosing of drugs that treat neurological diseases across the pediatric age spectrum. This platform combines: 1) In vitro models of the BBB; 2) Opportunistic plasma and CSF pharmacokinetic (PK) studies in children with external ventricular drains (EVDs). EVDs therapeutically remove CSF from the patient and permit non-invasive, serial CSF sampling to measure drug concentrations; 3) Physiologically-based pharmacokinetic modeling (PBPK) to predict plasma and CSF drug exposure in children. PBPK models can be modified to reflect differences in age and disease state. The principal investigator (PI) has a background in chemical and biomolecular engineering, in vitro systems, and modeling and simulation, and is conducting an ongoing plasma and CSF PK study in children with EVDs. To elucidate mechanisms of drug passage into the CSF and to optimize CNS drug dosing in children, the PI will pursue training through the K99/R00 Pathway to Independence Award mechanism at the University of Utah. To guide this training, an experienced mentorship team will provide expertise in clinical trials, in vitro models, membrane transporters, and sophisticated pharmacometric methods. In the mentored phase, in vitro BBB models will measure BBB permeability of five drugs commonly used in children in the context of age and disease. These measurements and information from the literature will inform pediatric CNS-PBPK models of these drugs in children. Then, CNS-PBPK models will be optimized using serial plasma and CSF PK measurements from children with EVDs across disease states and the pediatric age spectrum, and optimal dosing regimens will be determined. In the independent phase, the PI will conduct a prospective PK and safety trial to validate optimal, patient-specific dosing regimens for two drugs targeting the CNS in children. This work wil...