Linking Suspension Nasal Spray Drug Deposition Patterns to Pharmacokinetic Profiles: A Proof-of-Concept Study Using Computational Fluid Dynamics

Abstract

The objective of this study is to link regional nasal spray deposition patterns of suspension formulations, predicted with computational fluid dynamics (CFD), to in vivo human pharmacokinetic (PK) plasma concentration profiles. This is accomplished through the use of CFD simulations coupled with compartmental PK modeling. Results showed a rapid initial rise in plasma concentration that is due to the absorption of drug particles deposited in the nasal middle passages, followed by a slower increase in plasma concentration that is governed by the transport of drug particles from the nasal vestibule to the middle passages. Although drug deposition locations in the nasal cavity had a significant effect on the shape of the concentration profile, the absolute bioavailability remained constant provided that all of the drug remained in the nose over the course of the simulation. Loss of drug through the nostrils even after long time periods resulted in a significant decrease in bioavailability and increased variability. The results of this study quantify how differences in nasal drug deposition affect transient plasma concentrations and overall bioavailability. These findings are potentially useful for establishing bioequivalence for nasal spray devices and reducing the burden of in vitro testing, pharmacodynamics and clinical studies.

A consensus research agenda for optimising nasal drug delivery

“…Devices may be designed to target a specific site within the nasal cavity with the aim of optimizing © pharmacokinetics. Device, formulation and patient-related variables influence regional deposition and several attempts have been made to model this in view of understanding and predicting drug deposition in the nasal cavity [16]. There are instances when special product designs may be required for particular delivery needs, e.g.…”

“…Although the nose is generally regarded as a single compartment in pharmacokinetic modeling © , clearance rates may vary from different deposition sites. Mechanistic models are increasingly being used in drug delivery science and can pull together deposition, dissolution, clearance and permeability data in a combinatorial approach which utilize © a mix of experimental data and simulations [16,32]. Such an approach could be used to determine the interplay and biological relevance of dissolution and mucociliary clearance.…”

Use of computational fluid dynamics deposition modeling in respiratory drug delivery

“…Traditionally, this has been modeled with 1D or further simplified lung deposition predictions linked to PK or physiologically based (PB) pharmacokinetic models. However, research efforts are in progress to link CFD, or other mechanistic deposition models, with mechanistic simulations of dissolution, absorption and clearance, followed by traditional PK or PB-PK models to give a more accurate prediction of drug concentrations throughout the body [176, 177]. Linking CFD predictions of nasal uptake with a PK model of drug distribution was initially performed for tissue uptake of toxic gases [178].…”

Effects of thermal airflow and mucus-layer interaction on hygroscopic droplet deposition in a simple mouth–throat model

“…Furthermore, Rygg et al (2016a) investigated the effect of the particle size on the drug absorption using their model. Rygg et al (2016b) further coupled a compartmental pharmacokinetic model with this CFD model to investigate the transient pharmacokinetic plasma concentration change.…”