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

Abstract

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.

Fig. 1

General anatomical features of the lateral wall of the human nasal cavity. NV Nasal vestibule, IT inferior turbinate, MT middle turbinate, ST superior turbinate

Fig. 2

PK model of remoxipride delivered through IN administration. Compartment numbers are shown between brackets. Two absorption compartments exist, which describe absorption of drug into the central compartment (systemic circulation) and another one which describes direct drug absorption into the brain (direct nose-to-brain transport). The central compartment represents the remoxipride concentrations in plasma. Distribution of drug into other tissues and organs is described by the peripheral compartment. Lastly, the brain compartment represents drug concentrations in the ECF (34). Parameter values are provided in Table III

Fig. 3

Mechanism-based PK-PD model of remoxipride delivered in rats via IN drug administration. The PK part was based on the compartment model of Stevens et al. (2011) (34) and the PD part on a pool model developed by Movin-Osswald et al. (1995) (67)

Fig. 4

Global overview of steps in development of translational PK-PD models, as exemplified for remoxipride (34,67). First, a rat PK model is developed on data following IV administration only, followed by inclusion of also PD data, and simulated data by the model are validated on observed data (a). Then, these models are further developed to include IN administration in the rat, and simulated data are validated on their prediction of obtained PK and PK-PD data following IN administration (b). Subsequently, the rat IV PK and PK-PD models are “humanized” by appropriated scaling and simulated data by the humanized model is validated on obtained human PK and PK-PD data (c). Finally, it would be possible to further develop the humanized PK and PK-PD model as developed for IV administration, by further scaling of nose characteristics from rat to human