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

Intranasal (IN) drug delivery could be a promising non-invasive route to reach the central nervous system (CNS) bypassing the blood-brain-barrier (BBB). This review critically examines the mechanisms involved, challenges in predicting outcome of nasal delivery, and future directions of applying physiologically based pharmacokinetic (PBPK) modelling for such predictions. The nasal cavity has distinct anatomical and physiological features in the olfactory and respiratory regions, which play an essential role in drug deposition and subsequent entry to the systemic circulations as well as general passage. However, since the biological composition of the olfactory and trigeminal nerves in the nasal area are 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 impact 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 they are available. Nevertheless, translation from in vitro experiments or animal studies into humans, requires addressing knowledge gaps in such systems parameters. Future investigations should be directed towards creation of the necessary missing information as much as refinement of the models themselves. Combining advanced computational techniques for drug deposition with better PBPK models could help improve the predictivity of clinical outcomes from IN delivery that are targeting the CNS.