Development of a predictive model for pediatric intranasal drug delivery with nasal sprays: Leveraging intersubject variability in anatomical dimensions, administration-related parameters, and airway patency.

In this study, we examined the correlation between anatomical dimensions, spray administration parameters, pressure drop across 40 pediatric nasal cavities, and in vitro posterior drug delivery (PDD) using Nasacort ALLERGY 24HR and FLONASE SENSIMIST nasal suspensions sprays, with different nozzle and actuation designs. The importance of each parameter and their interaction in the outcome (PDD) was evaluated. To do so, initially we measured anatomical and administration-related parameters, and the pressure drop of each cavity. Afterwards, a stepwise regression method was used to find a combination of parameters that can effectively predict the outcome. Two strong correlations, r2 = 0.802 and 0.895, were found between a combination of three explored parameters and the PDD of Nasacort and Flonase Sensimist, respectively. While, based on the p-values, the insertion depth was found to be the most influential parameter for determining the PDD with Nasacort, and the administration coronal angle was found to be the most important one for Flonase Sensimist, anatomical parameters, or an interaction between anatomical and administration parameters were among the five most important parameters for both sprays. Furthermore, variable importance assessment, based on the variance of the response, demonstrated the tip-to-INV distance as the most important parameter for Nasacort and coronal angle for Flonase Sensimist, while cross sectional area at the end of the anterior piece was the only parameter that found to be in the three most important parameters for both sprays. Having this in mind, as well as the wide range of PDD within the pediatric population, it can be concluded that the performance of targeted intranasal drug delivery, even when using a set of patient-specific administration parameters, is strongly influenced by the anatomical features of the subject. Additionally, comparing the key factors in predicting PDD in pediatric and adult population for Flonase Sensimist demonstrate no similarity between the influential parameters on PDD in the two age groups, which further emphasizes the importance of airway anatomy.