Prediction of Silver Diamine Fluoride Concentrations in Children Using Physiologically-based Pharmacokinetic Modeling

Objectives: Silver diamine fluoride (SDF) is used topically to prevent or arrest dental caries and has been tested in toddlers to elderly adults. Following SDF application, small quantities of silver can be swallowed and absorbed. To monitor silver concentrations, pharmacokinetic studies can be performed. However, pharmacokinetic studies are time-consuming, resource-intensive and challenging to perform in young children. Our goal was to develop a physiologically-based pharmacokinetic (PBPK) model to predict silver disposition in children.
Methods: The PBPK model for silver was developed using Simcyp software (version 17.0) based on information obtained from literature sources. The predictive performance of the model was assessed by comparing the predicted PK profiles and parameters with the observed data from published rat and human data following intravenous or oral silver administration.
Results: The predicted silver concentrations were within 2-fold of observed blood and tissue silver concentrations in rats and within the 95% confidence interval of observed plasma silver concentrations in healthy human adults. The PBPK model was applied to the pediatric population by accounting for developmental physiological changes. For a given SDF dose, the simulated peak plasma silver concentrations were 5.2-, 4.3-, 2.7-, 1.3-fold higher in children aged 1-2 years, 2-4 years, 5-10 years and 12-17 years, respectively, compared to adults. The half-life of silver was comparable in all ages and plasma and tissue silver concentrations were predicted to return to baseline levels within 10 days after SDF application.
Conclusions: Based on the predictions, younger children will have transiently higher silver plasma concentrations than adults, though smaller increases are expected if less SDF is applied.