Pharmacokinetics of Advantage Arrest in Children

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).

Study Overview

• Status: Completed
• Conditions: Dental Caries
• Intervention / Treatment: Drug: Silver Diamine Fluoride

Detailed Description

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 Subjects will be treated with Advantage Arrest and have one blood sample withdrawn at a randomly assigned time point.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
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94158
      • University of California San Francisco Clinical and Translational Science Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 13 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Serum Fluoride Concentrations	Overall average of measured serum fluoride concentrations at the various timepoints.	Collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application

Collaborators and Investigators

• Sponsor: Advantage Silver Dental Arrest, LLC
• Collaborators: University of California, San Francisco
• Investigators: Principal Investigator: Hellene Ellenikiotis, DDS, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2019
• Primary Completion (Actual): March 31, 2020
• Study Completion (Actual): March 31, 2020

Study Registration Dates

• First Submitted: November 28, 2019
• First Submitted That Met QC Criteria: December 4, 2019
• First Posted (Actual): December 5, 2019

Study Record Updates

• Last Update Posted (Actual): March 10, 2022
• Last Update Submitted That Met QC Criteria: March 9, 2022
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: pharmacokinetics; child; silver diamine fluoride
• Additional Relevant MeSH Terms: Stomatognathic Diseases; Tooth Demineralization; Tooth Diseases; Dental Caries; Physiological Effects of Drugs; Protective Agents; Cariostatic Agents; Fluorides
• Other Study ID Numbers: 2019-06-23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No