Naloxone hydrochloride (HCl) nasal spray was approved in the United States in 2015, but only two generic products of naloxone HCl nasal spray have been approved. For this study, physiologically based pharmacokinetic (PBPK) modeling was applied to identify the sensitivity of model parameters that may impact pharmacokinetics (PK) metrics for naloxone nasal spray. The model predictions were verified against naloxone plasma concentration data from clinical PK studies for naloxone HCl nasal spray, which showed reasonable agreement. A sensitivity analysis demonstrated that the model parameters with the largest influence on PK metrics were nose percent drug unbound in mucus, extra-thoracic percent drug unbound in mucus, nose permeability, and mucociliary clearance time. The model demonstrated its ability to identify key process parameters for drug absorption and further experimental data are warranted to confirm the findings. The developed naloxone models may serve as useful tools for understanding nasally delivered naloxone.
Learning Objectives:
Explain the purpose, model structure, and approach for PBPK modeling of nasal drug products including naloxone HCl nasal spray formulations.