Mathematical Modeling and Simulation to Investigate the CNS Transport Characteristics of Nanoemulsion-Based Drug Delivery Following Intranasal Administration.
PURPOSE
Despite encouraging preclinical results, mechanisms of CNS drug delivery following intranasal dosing of nanoemulsions remain incompletely understood. Herein, the transport characteristics of intranasally administered nanoemulsions are investigated using mathematical modeling and simulation.


METHODS
A compartmental model was developed to describe systemic and brain pharmacokinetics of drug solutions following intranasal dosing in rodents. The association between transport processes and CNS drug delivery was predicted using sensitivity analysis. Published pharmacokinetic data for four drugs; dosed as a nanoemulsion and aqueous solution were modeled to characterize differences in transport processes across formulations.


RESULTS
The intranasal model structure performed in a drug agnostic fashion. Sensitivity analysis suggested that though the extent of CNS drug delivery depends on nasal bioavailability, the CNS targeting efficiency is only sensitive to changes in drug permeability across the nasal epithelium. Modeling results indicated that nanoemulsions primarily improve nasal bioavailability and drug permeability across the olfactory epithelium, with minimal effect on drug permeability across the non-olfactory epithelium.


CONCLUSIONS
Using mathematical modeling we outlined dominant transport pathways following intranasal dosing, predicted the association between transport pathways and CNS drug delivery, predicted human CNS delivery after accounting for inter-species differences in nasal anatomy, and quantified the CNS delivery potential of different formulations in rodents.
['Kadakia|Ekta|E|', 'Bottino|Dean|D|', 'Amiji|Mansoor|M|http://orcid.org/0000-0001-6170-881X']
D000281:Administration, Intranasal D000818:Animals D001692:Biological Transport D001812:Blood-Brain Barrier D002490:Central Nervous System D003198:Computer Simulation D016503:Drug Delivery Systems D004655:Emulsions D006801:Humans D008954:Models, Biological D053758:Nanoparticles D009831:Olfactory Mucosa D004364:Pharmaceutical Preparations D051381:Rats D057170:Translational Research, Biomedical
modeling and simulation nanoemulsions CNS targeting Blood-brain barrier intranasal drug delivery