Silver Diamine Fluoride in Children Using Physiologically Based PK Modeling

Abstract

<jats:p> Silver diamine fluoride (SDF) is used topically to prevent or arrest dental caries and has been tested clinically 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. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict silver disposition in children. 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. 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 silver concentrations were 5.2-, 4.3-, 2.7-, and 1.3-fold higher in children aged 1 to 2, 2 to 4, 5 to 10, and 12 to 17 y, respectively, compared to adults. As silver is reportedly excreted in the bile, the half-life of silver was comparable in all ages and plasma and tissue silver concentrations were predicted to return to baseline levels within 2 wk after SDF application. The simulation in children suggests that conventional SDF application to teeth to prevent or arrest dental caries results in plasma and tissue silver concentrations lower than toxic concentrations. PBPK modeling offers a novel approach to studying dental exposures in younger children, where pharmacokinetic studies would be difficult to conduct. </jats:p>

The use of silver diamine fluoride in a children's hospital: Critical analysis and action protocol

“…In a study on adults, Vasquez et al ( 2012 ) described the pharmacokinetics of SDF after oral application, concluding that serum concentrations of fluoride and silver demonstrated a low risk of toxicity when used only occasionally in this population. In a study on rats, Chen et al ( 2020 ) suggested that the conventional application of SDF on the teeth to prevent or stop dental caries results in silver concentrations in plasma and tissue that were far below toxic levels.…”

Revisiting Fluoride in the Twenty-First Century: Safety and Efficacy Considerations

“…Recent studies, however. have explored the possible toxic effects of silver(I) ion exposure from SDF [ 38 ]. The silver content of small amounts of SDF used to treat tooth decay results in a very low exposure, and therefore systemic silver toxicity should not represent a major concern to clinicians.…”

Annual review of selected scientific literature: A report of the Committee on Scientific Investigation of the American Academy of Restorative Dentistry

“…One aticle addressed potential toxicity of SDF based on a pharmacokinetic model to predict silver disposition in children. 300 The mathematical model was assessed by comparing the predicted values of physiologic silver concentrations with data from published animal and human studies after the oral ingestion of silver. The mathematically predicted silver concentrations were within the 95% confidence interval of observed plasma and tissue concentrations in the animal and human data.…”