Pharmacokinetics of Advantage Arrest in Children

Study Overview
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Brief Summary
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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).

Detailed Description
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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 Subjects will be treated with Advantage Arrest and have one blood sample withdrawn at a randomly assigned time point.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.

Official Title
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Pharmacokinetics of Advantage Arrest in Children

Conditions
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Dental Caries

Intervention / Treatment
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* Drug: Silver Diamine Fluoride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy. At least one carious lesion. Exclusion Criteria: Oral mucositis Any ulcerative lesions Hypersensitivity to silver Hypersensitivity to fluoride. SDF treatment within 3 months.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open label exposure--response study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Advantage Arrest<br>38% silver diamine fluoride, topical, 1 drop, single application | Drug: Silver Diamine Fluoride<br>* 38% aqueous silver diamine fluoride [Ag(NH3)]2F, CAS RN 33040-28-7<br>* Other names: Advantage Arrest;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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). | 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). | Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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). | Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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child, pharmacokinetics, silver diamine fluoride