Scientific Publications by FDA Staff

Respir Drug Del 2016;1:175-84

Bioequivalence testing: can systemic pharmacokinetic profiles from corticosteroid nasal sprays be used to elucidate local drug deposition within the nose?

Longest P, Rygg A, Hindle M

To establish bioequivalence (BE) between a generic suspension formulation nasal spray and its reference listed product, proof of equivalent local delivery is required. For a poorly soluble drug such as mometasone furoate, pharmacokinetic (PK) methods could potentially be used to determine local delivery if there was an established link between local and systemic concentrations. The objective of this study was to implement a newly developed complete nasal transport model to investigate the theoretical relationships between nasal spray drug deposition in the nasal cavity and plasma drug concentrations. Realistic in vitro tests were first used to determine spray characteristics and validate computational fluid dynamics (CFD) predictions of local deposition within the nasal cavity. A new CFD transport model implemented these deposition profiles as the starting locations for subsequent modeling of suspended drug particle (mometasone furoate) dissolution, absorption, and clearance in a defined nasal surface geometry. Once absorbed into the respiratory epithelium, a PK model was used to predict drug plasma concentration profiles. Model parameters and predictions were validated using in vivo data for both nasal clearance rates and drug plasma profiles. The model was then used to demonstrate the association between Cmax and middle passage (MP) nasal deposition of the model drug. For a proprietary suspension nasal spray like Nasonex, the model showed that both MP deposition and Cmax were highly sensitive to changes in patient-use parameters, such as spray nozzle insertion angle, nasal inhalation, and nose blowing, which could make the establishment of bioequivalence problematic. As an alternative approach, it is suggested that a small PK (or radiological imaging) study be used to first validate a combination in vitro-in silico approach and this new combination method be used for establishing the local delivery component of BE testing.