Challenges and Opportunities for Incorporating Physiological Information into Pharmacokinetic Models of Intranasal Drug Delivery to the Brain: A Review of the Current Status and Future Trajectories.

Intranasal (IN) drug delivery is a promising noninvasive route for targeting the central nervous system (CNS) bypassing the blood-brain-barrier (BBB). This review critically examines the underlying mechanisms, challenges in predicting nasal drug delivery outcomes, and future directions for applying physiologically based pharmacokinetic (PBPK) modeling to support such predictions. The nasal cavity comprises distinct anatomical and physiological features in the olfactory region (upper posterior part of the nasal cavity) and the respiratory region (middle part and lateral walls of the nasal cavity), both of which play essential roles in drug deposition, systemic absorption, and general passage. However, since the biological composition of the olfactory and trigeminal nerves in the nasal area is not well-known, the prediction of drug absorption to systemic circulation from nasal mucosa or direct transport from nose to brain are fraught with many challenges. Thus, addressing the impacts of drug permeability, mucociliary clearance, enzymatic degradation, and nasomucosal toxicity are still essential challenges when developing nasal formulations for drugs. PBPK models have the capability of integrating complex anatomical, physiological, and biological aspects of the systems when such data are available. Nevertheless, translation from in vitro experiments or animal studies into humans requires addressing knowledge gaps in systems parameters. Future investigations should focus on generating the necessary missing information as well as refining the models. Application of advanced modeling methods for simulation of drug deposition, in conjunction with refined nasal PBPK models, is envisaged to improve the prediction of clinical outcomes for CNS targeted IN drug delivery.