Pharmacokinetics of Advantage Arrest in Children

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04186663

Enrollment

Registered

2019-12-05

Start date

2019-08-01

Completion date

2020-03-31

Last updated

2022-03-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Dental Caries

Keywords

child, pharmacokinetics, silver diamine fluoride

Brief summary

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

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 Subjects will be treated with Advantage Arrest and have one blood sample withdrawn at a randomly assigned time point.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

Interventions

DRUGSilver Diamine Fluoride

38% aqueous silver diamine fluoride \[Ag(NH3)\]2F, CAS RN 33040-28-7

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

Open label exposure--response study

Eligibility

Sex/Gender

ALL

Age

3 Years to 13 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
Silver Half-life	Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application	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).
Predicted Peak Serum Silver Concentration (Cmax)	Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application	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).
Predicted Time to Peak Serum Silver Concentration (Tmax)	Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application	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).

Secondary

Measure	Time frame	Description
Serum Silver Exposure (AUC)	Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application	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).
Apparent Oral Clearance of Silver (CL/F)	Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application	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.
Apparent Volume of Distribution of Silver (V/F)	Based on data collected at 2, 4, 6, 24, 48, 96, and 168 hours post-SDF application	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.

Other

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

Countries

United States

Participant flow

Participants by arm

Arm	Count
Advantage Arrest 38% silver diamine fluoride, topical, 1 drop, single application Silver Diamine Fluoride: 38% aqueous silver diamine fluoride \[Ag(NH3)\]2F, CAS RN 33040-28-7	55
Total	55

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Lost to Follow-up	1
Overall Study	Unable to complete blood draw	3

Baseline characteristics

Characteristic	Advantage Arrest
Age, Continuous	7.7 years STANDARD_DEVIATION 2.9
Ethnicity (NIH/OMB) Hispanic or Latino	24 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	25 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	6 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	11 Participants
Race (NIH/OMB) Black or African American	8 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	25 Participants
Race (NIH/OMB) White	11 Participants
Region of Enrollment United States	55 participants
Sex: Female, Male Female	25 Participants
Sex: Female, Male Male	30 Participants
Weight (kg)	32.6 kg STANDARD_DEVIATION 16.5

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 55
other Total, other adverse events	0 / 55
serious Total, serious adverse events	0 / 55

Outcome results

Primary

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).