Department of Pharmaceutics, University of Washington, Seattle, WA, USA.
Department of Oral Health Sciences, University of Washington, Seattle, WA, USA.
J Dent Res. 2020 Jul;99(8):907-913. doi: 10.1177/0022034520917368. Epub 2020 May 6.
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.
银胺氟化物（SDF）被局部用于预防或抑制龋齿，并已在幼儿至老年人中进行了临床测试。在 SDF 应用后，少量的银可以被吞咽和吸收。为了监测银浓度，可以进行药代动力学研究。然而，药代动力学研究既耗时又资源密集，并且在幼儿中难以进行。本研究的目的是开发一种基于生理学的药代动力学（PBPK）模型来预测儿童体内的银分布。使用 Simcyp 软件（版本 17.0）基于文献来源获得的信息，建立了银的 PBPK 模型。通过比较静脉内或口服银给药后从已发表的大鼠和人体数据获得的预测 PK 曲线和参数与观察数据，评估了模型的预测性能。预测的银浓度与大鼠血液和组织中的观察到的银浓度在 2 倍以内，与健康成年人血浆中的观察到的银浓度在 95%置信区间内。通过考虑发育生理变化，将 PBPK 模型应用于儿科人群。对于给定的 SDF 剂量，与成年人相比，1 至 2 岁、2 至 4 岁、5 至 10 岁和 12 至 17 岁的儿童的模拟峰值银浓度分别高 5.2、4.3、2.7 和 1.3 倍。由于银据报道在胆汁中排泄，因此所有年龄段的银半衰期都相似，并且在 SDF 应用后 2 周内，血浆和组织中的银浓度预计将回到基线水平。在儿童中的模拟表明，常规应用 SDF 于牙齿以预防或抑制龋齿会导致血浆和组织中的银浓度低于毒性浓度。PBPK 建模为研究年幼儿童的牙科暴露提供了一种新方法，在这些儿童中进行药代动力学研究是困难的。
