Pharmacokinetics of Neostigmine and Glycopyrrolate

Pharmacokinetics of Neostigmine and Glycopyrrolate After Intravenous and Transcutaneous Administration by Iontophoresis

A group of 6 able-bodied healthy volunteers will receive Neostigmine (NEO) and Glycopyrrolate (GLY) intravenously and via 2 methods of Iontophoresis (ION): one-patch and two-patch administration, with subsequent blood draws over 1 hour in order to measure the pharmacokinetic behavior of the drugs in-vivo.

Study Overview

• Status: Active, not recruiting
• Conditions: Constipation; Spinal Cord Injuries; Neurogenic Bowel; Fecal Incontinence
• Intervention / Treatment: Drug: Combination of Neostigmine and Glycopyrrolate; Device: I-Box by Dynatronics

Detailed Description

The maximum dose of NEO is limited to 10.0 mg and the dose of GLY to 2.0 mg per subject per administration. Subjects will be asked to arrive at the Spinal Cord Research Center at the JJP VAMC (Room 7A-13) on the day of their appointment. On Day 1, following the obtainment the subject's consent, filling out a MoCA cognitive assessment and establishing an IV access point, administration of the medications via IV will be performed. The study design will consist of a Day 1 visit to determine the pharmacokinetic profiles of the IV doses of NEO and GLY. During the second visit, at least 24 hours later, NEO (0.07 mg/kg) and GLY (0.014 mg/kg), applied separately to two patches, will be simultaneously delivered by transdermal administration by ION for 20 minutes. During the third and final visit, at least 24 hours following the second visit, a single patch containing 0.07 mg/kg of NEO and 0.014 mg/kg of GLY will be applied to the skin and delivered by transdermal administration by ION for 20 minutes..

Heart rate, bowel sounds, blood pressure and symptoms will be recorded at 0, 2, 4, 7, 10, 20, 40, 60 minutes of the initiation of the IV push and at 0, 10, 20, 40 and 60 minutes after the initiation of ION. Bowel evacuation time and time after the completion of delivery (by either ION or IV) will be recorded throughout the study visit, as described in Table 2. The subject will assume his/her normal bowel evacuation (BE) position until a bowel movement occurs; privacy draping and privacy will be provided at the time of BE. The subjects will be monitored for a minimum of 60 minutes. A minimum of two research personnel will be present during the study visit to record all of data and perform the tasks required.

After the start a 30 second IV push of NEO which will be followed by a NS flush (12 mL), and then a 30 second IV push of GLY which will be followed by a NS flush (12 mL), venous blood (2 mL) will be drawn into a gold-topped vial at 2, 4, 7, 10, 20, 40 and 60 minutes. Identical technique blood draws will be performed at 10, 20, 30, 40 and 60 minutes after the start of ION. Upon drawing, the blood will be placed in an ice bath and spun using a cooled centrifuge within 5 minutes of collection. Upon completion of 5 minutes of centrifugation, the resulting serum will be aliquoted into two separate vials, with equal volumes and labelled with date, time of draw, associated procedure, NEO or GLY testing destination and the subject's unique identifier. The transfer vials will be inserted into dry ice for at least 10 minutes, after which they will be placed into the -80 degrees Celsius freezer. Plasma levels of NEO and of GLY will be batched and measured at a later date. A file designating the tubes with random numbers associated with the draw times will be created for each subject to conceal the sequence of draw and to attempt the removal of possible bias during the measurement and recording of the concentrations of NEO and GLY (SUNY Downstate Albany Research Laboratory using GE LC-MRM detector).

Proposed Doses:

Day 1: 0.02 mg/kg NEO and 0.004 mg/kg GLY via IV

Day 2: 0.07 mg/kg NEO and 0.014 mg/kg GLY via ION (Two patch administration)

Day 3: 0.07 mg/kg NEO and 0.014 mg/kg GLY via ION (One patch administration)

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Anton Sabiev, MD; Phone Number: 917 717 4643; Email: anton.sabiev@va.gov
• Study Contact Backup: Name: Mark Korsten, MD; Phone Number: 6753 718 584 5000; Email: mark.korsten@va.gov

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10468
      • James J Peters VA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Male or Female
• Age 18-70 years

Exclusion Criteria:

• Previous adverse reaction or hypersensitivity to electrical stimulation,
• Known sensitivity to neostigmine or glycopyrrolate,
• History of mechanical obstruction of the GI or urinary tract,
• Myocardial infarction within 6 months of trial,
• Malignant and/or Uncontrollable Hypertension Defined by a blood pressure reading of 160/100 mmHg or higher with or without taking 3 or more different classes of anti-hypertensive medications,
• Organ damage (heart & kidney) and/or TIA-CVA as a result of hypertension,
• Known past history of coronary artery disease or bradyarrhythmia,
• Symptomatic orthostatic hypotension
• Deep brain stimulation
• Pregnancy (women who are sexually active and of childbearing potential must utilize a method of contraception and agree to maintain a contraceptive method until completion of the study),
• Lactating, nursing females
• Inability to provide informed consent signaled by MoCA cognitive test score of 20 or less,
• History of ingrown hair folliculitis,
• Concurrent illness and fever,
• Concurrent participation in a research study,
• VA employee.

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: Primary; 6 Subjects will receive all 4 types of medication administration in random sequence	Drug: Combination of Neostigmine and Glycopyrrolate; Intravenous or transdermal; Device: I-Box by Dynatronics; Electric field conducting drugs through the skin without compromising its integrity; Other Names: Iontophoresis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum concentrations of Neostigmine and Glycopyrrolate within 1 hour post-administration	Measurement of serum concentration of Neostigmine and of Glycopyrrolate to determine pharmacokinetic profiles	Within Two Hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence or absence of headache, dry mouth, muscle twitching and abdominal cramps.	Determining safety of drug via presence or absence of headache, dry mouth, muscle twitching, and abdominal cramps as reported by the subjects	Within 1 hour of administration

Collaborators and Investigators

• Sponsor: James J. Peters Veterans Affairs Medical Center
• Investigators: Principal Investigator: Christopher P Cardozo, MD, James J. Peters Veterans Affairs Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2020
• Primary Completion (Actual): February 17, 2023
• Study Completion (Estimated): September 28, 2024

Study Registration Dates

• First Submitted: July 19, 2019
• First Submitted That Met QC Criteria: July 19, 2019
• First Posted (Actual): July 22, 2019

Study Record Updates

• Last Update Posted (Actual): October 12, 2023
• Last Update Submitted That Met QC Criteria: October 10, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Constipation; Transdermal; Intravenous; Pharmacokinetic; Neostigmine; Glycopyrrolate; Bowel Control; Mass Spectroscopy; Stool Incontinence
• Additional Relevant MeSH Terms: Digestive System Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Signs and Symptoms, Digestive; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Trauma, Nervous System; Spinal Cord Diseases; Constipation; Spinal Cord Injuries; Neurogenic Bowel; Fecal Incontinence; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Enzyme Inhibitors; Adjuvants, Anesthesia; Cholinesterase Inhibitors; Parasympathomimetics; Glycopyrrolate; Neostigmine
• Other Study ID Numbers: KOR-18-16

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: Yes