Mathematical Modeling and Simulation to Investigate the CNS Transport Characteristics of Nanoemulsion-Based Drug Delivery Following Intranasal Administration.

Abstract

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. 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. 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. 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.