An effective PBPK model predicting dissolved drug transfer from a representative nasal cavity to the blood stream

Abstract

Predicting the fate of nasally administered drugs is important for the understanding and possible improvement of in vivo performance. When computational fluid-particle dynamics (CFPD) results are coupled with a physiologically based pharmacokinetic (PBPK) model, drug concentrations in the blood stream can be obtained. Specifically, hybrid CFPD-PBPK simulations can predict inhaled particle transport, deposition, and uptake in the nasal mucus layers and subsequently absorbed drug migration from the nasal cavity to the blood stream.The computer simulation results of Chari et al. (2021) were used as input to a basic PBPK model to track the deposited and dissolved drugs from the nasal cavities to the blood stream. Employing the open-source toolbox OpenFOAM, our PBPK model predictions were compared with experimental in vivo data sets for different corticosteroids. The relative differences between experimental and simulated values of PK metrics, following administration of mometasone furoate nasal spray, were all 7% or less. Drug plasma concentrations based on different drug parameters, such as solubility and partition coefficient, were studied as well. The drug concentration in the plasma was found to increase with an increase in drug solubility (Cs = 0.02 mg/ml, 0.1 mg/ml, 0.2 mg/ml). The same trend was observed for different partition coefficients (Kow = 5e-3, 2, 5000), where the plasma concentration curve peaked for a partition coefficient of 5000. It was also observed that drug dosage controls the amount of residual drug concentrations in the plasma with the passage of time. Two different drug dosages were studied, ie, 50 μg and 800 μg, with the former being completely absorbed in the plasma after 8 h; however, in the latter case the drug was not completely absorbed after that time interval. These modeling and simulation results are useful for planning aspects in drug development, as the predictions provide physical insight to differences in device, formulation, and dosage selection.