The purpose of this study is to characterize basic PK parameters (Cmax, t1/2, AUC) in healthy children to contribute to evidence for the safety of Advantage Arrest, consistent with Guidance for Industry--Exposure--Response Relationships (April 2003).
This is a topical agent where the active ingredients are applied to the teeth and eventually swallowed and may be absorbed through the GI tract or excreted. Minimal amounts are absorbed through the oral mucosa. Serum concentrations of silver and fluoride will be be proportional to the dose of silver and fluoride administered topically to the teeth as part of Advantage Arrest. This is an open label exposure-response study with up to 50 healthy children ages 3-13 years of age. Subjects will be treated with Advantage Arrest and have one blood sample withdrawn at a randomly assigned time point. A minimum of 3 subjects per time point at 2,4,6,24,48,96 and 168 hours. Serum samples will be analyzed for F and Ag.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
59
38% aqueous silver diamine fluoride \[Ag(NH3)\]2F, CAS RN 33040-28-7
University of California San Francisco Clinical and Translational Science Institute
San Francisco, California, United States
Predicted Peak Serum Silver Concentration (Cmax)
As only a single blood sample was obtained from each child, serum silver concentration versus time data were analyzed simultaneously using population pharmacokinetic analysis with nonlinear mixed effects modeling. The parameters estimated were the apparent volume of distribution (V/F) and apparent oral clearance (CL/F). The rate constant of absorption (ka) was fixed to 23.7 day-1. The predicted peak serum silver Cmax was calculated using Cmax = Dose/(V/F)\*exp\^(-k⋅tmax ), where k = (CL/F)/(V/F) and tmax = \[ln(ka/k)\]/(ka-k).
Time frame: Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application
Predicted Time to Peak Serum Silver Concentration (Tmax)
As only a single blood sample was obtained from each child, serum silver concentration versus time data were analyzed simultaneously using population pharmacokinetic analysis with nonlinear mixed effects modeling. The parameters estimated were the apparent volume of distribution (V/F) and apparent oral clearance (CL/F). The rate constant of absorption (ka) was fixed to 23.7 day-1. The predicted time to peak concentration was calculated using tmax = \[ln(ka/k)\]/(ka-k), where k = (CL/F)/(V/F).
Time frame: Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application
Silver Half-life
As only a single blood sample was obtained from each child, serum silver concentration versus time data were analyzed simultaneously using population pharmacokinetic analysis with nonlinear mixed effects modeling. The parameters estimated were the apparent volume of distribution (V/F) and apparent oral clearance (CL/F). The rate constant of absorption (ka) was fixed to 23.7 day-1. The half-life of silver was calculated using half-life = ln(2)/k, where k = (CL/F)/(V/F).
Time frame: Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application
Apparent Oral Clearance of Silver (CL/F)
As only a single blood sample was obtained from each child, serum silver concentration versus time data were analyzed simultaneously using population pharmacokinetic analysis with nonlinear mixed effects modeling. The apparent oral clearance of silver (CL/F) was an estimated parameter.
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Time frame: Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application
Apparent Volume of Distribution of Silver (V/F)
As only a single blood sample was obtained from each child, serum silver concentration versus time data were analyzed simultaneously using population pharmacokinetic analysis with nonlinear mixed effects modeling. The apparent volume of distribution (V/F) was an estimated parameter.
Time frame: Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application
Serum Silver Exposure (AUC)
Area under the curve of silver. As only a single blood sample was obtained from each child, serum silver concentration versus time data were analyzed simultaneously using population pharmacokinetic analysis with nonlinear mixed effects modeling. The parameters estimated were the apparent volume of distribution (V/F) and apparent oral clearance (CL/F). The rate constant of absorption (ka) was fixed to 23.7 day-1. The area under the curve was calculated using AUC = Dose/(CL/F).
Time frame: Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application