Assessment of Methadone Dose Taken Using Electrochemistry

Study Overview
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Brief Summary
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Proof of concept: Pilot Study A Pilot, proof of concept, observational study with a long-term goal to develop a minimally invasive wearable Remote Medication Monitor (RMM) that provides continuous, real-time data on methadone levels in interstitial fluid (ISF). An RMM could be used as a medication adherence monitor and would allow for the physician, counselor, patient, or family member to remotely verify that a physician-prescribed dose has been taken.

Detailed Description
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The investigator will conduct a non-randomized, non-blinded, feasibility study at a single center in the United States. The study will include up to 20 subjects of an equal number of male and female adults (ages 18-70) who have a prescription for methadone for chronic pain. In Aim 1, the investigator will determine if an RMM can assess the status of taking a prescribed dose of methadone, using biosamples (i.e., ISF, blood) collected from subjects and tested in a laboratory setup. Biosample collections and pharmacokinetic monitoring will take up to 6 consecutive hours. By completing this aim, the investigator will determine if a physician is able to recognize the peak and trough of a methadone dose using ex vivo Differential Pulse Voltammetry (DPV). In Aim 2, the investigator will determine if an RMM can continuously assess the status of taking a prescribed dose of methadone over time, by inserting the intradermal microneedle sensing elements into the subjects' skin. The electronics for the RMM prototypes will consist of commercially available benchtop potentiostats like the PalmSens Sensit BT (https://www.palmsens.com/product/palmsens4/) or CH Instruments 660D (https://www.chinstruments.com/) and will not be in direct contact with the skin. Biosample collections (i.e., ISF, blood) and pharmacokinetic monitoring will occur over a 6-hour period. By completing this aim, the investigator will determine if a physician is able to recognize the pharmacokinetic profile of a taken dose of methadone. The physician will see a dosing curve display generated from intradermal microneedle sensing elements that are worn continuously on the skin. Completion of Aims 1-2 will require two separate visits.

Official Title
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Assessment of Methadone Dose Taken Using Electrochemistry

Conditions
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Methadone Toxicity, Methadone Overdose, Pain, Chronic, Drug Metabolism, Poor, CYP2D6-Related, Metabolism Medication Toxicity

Intervention / Treatment
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* Device: ISF extraction device 1
* Diagnostic Test: Measurement of Methadone in the Interstitial Fluid (ISF) before and after prescribed dose taken ex vivo
* Device: Measurement of Methadone in the Interstitial Fluid before and after prescribed dose taken in vivo
* Drug: Measurement of Methadone in ISF before and after taking prescribed dose
* Device: ISF Extraction Device 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70 A prescription for methadone for chronic pain at a dose of 10mg or more for at least one week. Taking methadone as prescribed during the last 4 days before consent to participate in the study. Exclusion Criteria: Age <18 or >70 A condition preventing or complicating ISF collection dermatological (skin) condition immunodeficiency recent blood donation anemia end stage renal disease liver cirrhosis cancer congestive heart failure bleeding diathesis tuberculosis (TB) Any active severe depression suicidal ideation mania symptoms Pregnancy Intending to become pregnant during the course of the study Enrolled in a substance use disorder treatment program Under a conservatorship.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Visit Day 1<br>AIM 1 : Determine if an RMM can assess the status of taking a prescribed dose of methadone. To complete this aim, the peak and trough concentrations of a witnessed methadone dose will be assessed in ISF collected through the surface of the skin using existing ISF extraction methods and assessed outside the body via differential pulse voltammetry (DPV). We hypothesize that the peak and trough blood samples will correlate with the level of methadone in collected ISF. | Device: ISF extraction device 1<br>* FDA approved microneedle attached to blotter paper tested for ability to extract 1ul of interstitial fluid<br>* Other names: Samplimy;Diagnostic Test: Measurement of Methadone in the Interstitial Fluid (ISF) before and after prescribed dose taken ex vivo<br>* Measurement of Methadone and its metabolites in interstitial fluid with Liquid Chromatography - Mass Spectroscopy (LC-MS) and Electrochemical Assay<br>* Other names: dose taken peak-trough test;Drug: Measurement of Methadone in ISF before and after taking prescribed dose<br>* Measurement of methadone in ISF using DPV ex vivo versus in vivo . (Accuracy comparison - sensitivity, specificity, level of detection, and standard deviations )<br>* Other names: Comparing in vitro and in vivo approaches to determining a dose taken;|
| Visit Day 2<br>AIM 2 : Determine if an RMM can continuously assess the status of taking a prescribed dose of methadone over time. To complete this aim, the pharmacokinetic profile of a witnessed methadone dose will be assessed in ISF continuously from the surface of the skin using the RMM for up to 6 hours. We hypothesize that a clinician can recognize a dose taken from the continuous and real-time RMM measurements made in live ISF. | Device: ISF extraction device 1<br>* FDA approved microneedle attached to blotter paper tested for ability to extract 1ul of interstitial fluid<br>* Other names: Samplimy;Device: Measurement of Methadone in the Interstitial Fluid before and after prescribed dose taken in vivo<br>* Measurement of Methadone and its metabolites in ISF with LC-MS and DPV<br>* Other names: In vivo Differential Pulse Voltammetery ( DPV );Drug: Measurement of Methadone in ISF before and after taking prescribed dose<br>* Measurement of methadone in ISF using DPV ex vivo versus in vivo . (Accuracy comparison - sensitivity, specificity, level of detection, and standard deviations )<br>* Other names: Comparing in vitro and in vivo approaches to determining a dose taken;Device: ISF Extraction Device 2<br>* 2 hour periods of continuous ISF collection for analysis<br>* Other names: Kiffik;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Methadone Concentration in ISF before and after a dose | measure dermal interstitial fluid with LC-MS for methadone before and after a daily dose | 1 day | 
| Methadone Concentration in blood before and after a dose | measure blood for methadone with LC-MS before and after a daily dose | 1 day | 
| Concentration of Methadone in ISF with LC-MS versus Electrochemical Assay | measure ISF with two procedures (Liquid Chromatography - Mass Spectroscopy and Differential Pulse Voltammetry. | 2 days | 
| Concentration of Methadone in blood with LC-MS versus Electrochemical Assay | measure blood with two procedures (Liquid Chromatography - Mass Spectroscopy and Differential Pulse Voltammetry. | 2 days | 
| Pearson Correlation of Methadone between ISF and Blood | measure blood and ISF methadone with LC-MS and determine pearson correlation | 2 days | 
| Pearson Correlation between DPV and LC-MS ISF Methadone | measure ISF for methadone by LC-MS and DPV and determine Pearson correlation | 2 days | 
| Pearson Correlation between DPV and LC-MS ISF EDDP | measure ISF for EDDP by LC-MS and DPV and determine Pearson correlation | 2 days | 
| Pearson Correlation between DPV and LC-MS blood EDDP | measure blood for EDDP by LC-MS and DPV and determine Pearson correlation | 2 days | 
| EDDP concentration in ISF before and after daily dose of methadone | measure ISF for EDDP by LC-MS before and after daily dose of methadone | 1 day | 
| EDDP concentration in blood before and after daily dose of methadone | measure blood for EDDP by LC-MS before and after daily dose of methadone | 1 day | 
| EMDP concentration in ISF before and after daily dose of methadone | measure EMDP in ISF before and after daily dose of methadone | 1 day | 
| EMDP concentration in blood before and after daily dose of methadone | measure EMDP in blood by LC-MS before and after daily dose of methadone | 1 day | 
| Pearson Correlation of Methadone to Metabolite Ratio ( MMR ) between ISF and Blood using LC-MS | Calculate methadone to EDDP ratio of ISF and Blood and determine Pearson Correlation using LC-MS | 2 days | 
| Pearson Correlation of Methadone to Metabolite Ratio ( MMR ) between ISF and Blood using DPV | Calculate methadone to EDDP ratio of ISF and Blood and determine Pearson Correlation using DPV | 2 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics