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To investigate the potential added value of intranasal drug administration, preclinical studies to date have typically used the area under the curve (AUC) in brain tissue or cerebrospinal fluid (CSF) compared to plasma following intranasal and intravenous administration to calculate measures of extent like drug targeting efficiencies (%DTE) and nose-to-brain transport percentages (%DTP). However, CSF does not necessarily provide direct information on the target site concentrations, while total brain concentrations are not specific to that end either as non-specific binding is not explicitly considered. Moreover, to predict nose-to-brain transport in humans, the use of descriptive analysis of preclinical data does not suffice. Therefore, nose-to-brain research should be performed translationally and focus on preclinical studies to obtain specific information on absorption from the nose, and distinguish between the different transport routes to the brain (absorption directly from the nose to the brain, absorption from the nose into the systemic circulation, and distribution between the systemic circulation and the brain), in terms of extent as well as rate. This can be accomplished by the use of unbound concentrations obtained from plasma and brain, with subsequent advanced mathematical modeling. To that end, brain extracellular fluid (ECF) is a preferred sampling site as it represents most closely the site of action for many targets. Furthermore, differences in nose characteristics between preclinical species and humans should be considered. Finally, pharmacodynamic measurements that can be obtained in both animals and humans should be included to further improve the prediction of the pharmacokinetic-pharmacodynamic relationship of intranasally administered CNS drugs in humans.

the aaps journal

Emerging Insights for Translational Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Studies: Towards Prediction of Nose-to-Brain Transport in Humans