Pharmacokinetic Study of Single-Dose Modified Release Glipizide in Healthy Volunteers

Study Overview
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Brief Summary
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In vivo drug dissolution in the gastrointestinal (GI) tract is largely unmeasured. The purpose of this clinical study is to evaluate the in vivo drug dissolution and systemic absorption of modified release formulations of the BCS Class II drug Glipizide by direct sampling of stomach and small intestinal luminal content, blood, urine and feces. Also collection of physiologic data (such as pressure, temperature and GI transit time) from GI tract through an electronic pill taken by mouth called SmartPill. Expanding current knowledge of drug dissolution in vivo will help to establish physiologically relevant in vitro models predictive of drug dissolution.

Detailed Description
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This is an in vivo study designed to acquire human gastrointestinal (GI) physiology data from healthy subjects which are necessary for mechanistic absorption model development. Each subject will be asked to complete two phases. The first phase will include collection of fluids from stomach and gastrointestinal (GI) tract through intubation (putting a GI tube from mouth into stomach and intestines), blood, urine and feces, and measure glipizide concentrations. The second phase will not involve the intubation procedure. Instead, An electronic pill called SmartPill will be used. The pill is swallowed by mouth and collects physiologic data (such as pressure, temperature and GI transit time) as it travels through GI tract. Blood, urine and feces, will also be collected for measurement of glipizide concentrations. A minimum of 5 days will separate each of the two study phases. The objectives of this study are, as follows: Objective #1: To characterize the plasma, gastrointestinal fluid, urine, and feces concentrations of glipizide after oral administration of modified release formulations; Objective #2: To compare the pharmacokinetics of glipizide between the two modified release formulations; Objective #3: To compare the pharmacokinetics of glipizide with and without gastrointestinal intubation; Objective #4: To collect gastrointestinal physiology data in volunteers receiving an oral MR formulation of glipizide. These in vivo results will be used to validate in vitro dissolution methods and to support computational and mathematical modeling efforts, in order to develop an oral drug product optimization process that may be applied to future drugs to maximize oral drug safety and efficacy.

Official Title
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Open-Label, Randomized, Pharmacokinetic Study of Single-Dose Modified Release Glipizide in Healthy Volunteers

Conditions
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Human Gastrointestinal Physiology Data

Intervention / Treatment
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* Drug: Glucotrol XL 5Mg Extended-Release Tablet
* Drug: Glipizide ER 5 MG 24 HR Extended Release Oral Tablet
* Drug: Rifaximin 200Mg Tab
* Drug: 13C6-Glipizide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female adults age 18 to 55 years with BMI ranging from 18.5 to 35 kg/m2 inclusive Ability to independently provide an informed consent Demonstrate the ability to swallow a multivitamin pill that mimics a SmartPill capsule Negative serum pregnancy test (for women of child-bearing potential) Exclusion Criteria: Unable to independently provide an informed consent for themselves or mentally incapacitated. Physical disability (including blindness or deafness) that requires special arrangements. Significant clinical illness, including cardiovascular disease, neurological disease, organ failure, or malignancy in the opinion of the investigator Any surgical procedure within 3 weeks prior to screening History and/or presence of severe seasonal allergies or severe allergic diseases including drug allergies, food allergies and allergy against the SmartPill® device History and/or presence of hypersensitivity to any of the study drugs or the products' excipients History and/or presence of hypersensitivity to Sulfonamide derivatives History and/or presence of hypersensitivity to Lidocaine History and/or presence of hypersensitivity to rifaximin, rifamycin antimicrobial agents, or any of the components of XIFAXAN History and/or presence of hypersensitivity to acrylate or methacrylate, commonly used components of medical adhesives Any other factor, condition, or disease, including, but not limited to, cardiovascular, respiratory, hematological, renal, hepatic, or gastrointestinal disorders that may, in the opinion of the Investigator, jeopardize the safety of the patient, alter drug absorption and pharmacokinetics or impact the validity of the study results. Subjects with Type 1 Diabetes Mellitus (DM), diabetic ketoacidosis, with or without coma Subjects with Glucose 6-phosphate dehydrogenase (G6PD) deficiency History and/or presence of drug addiction or alcohol abuse within the past 12 months. History of significant psychiatric or neurological illness, including seizure disorders. Any medical or surgical conditions which might significantly interfere with the functions of gastrointestinal tract (e.g., gastric/intestinal bypass surgeries, fistulas, strictures, stenosis, or physiological/mechanical obstruction of the G.I tract, gastric bezoars, irritable bowel disease, crohn's disease, diverticulosis, or chronic narcotic use). History of dysphagia to liquids, food, or pills History of abdominal radiation therapy Pregnant or lactating females Any clinically significant abnormal lab values during screening in the opinion of the investigator. Use of alcohol and/or nicotine containing products 48 hours prior to dosing visits, and throughout PK sampling visits. Use of any medications and/or supplements, prescriptions or over the counter 1 week prior to beginning the study, and throughout the study except for birth control with approved methods of contraception when used consistently and correctly (Implants (i.e. Implanon, Nexplanon), Injectables (i.e. Depo-Provera), Combined, Oral Contraceptives, Intrauterine Devices (IUD's) (i.e. Mirena, ParaGard), and Sexual Abstinence are accepted). Use of aspirin or any blood thinner medications. Use of an implanted or portable electro-mechanical medical device such as a cardiac pacemaker or infusion pump. Volunteers unwilling or unable to take the proposed drugs or undergo G.I intubation Enrollment in a clinical trial in the past 30 days Current enrollment in a clinical trial with another study drug, vaccine or medical device Fasting blood glucose level < 80 mg/dL. Inability or unwillingness to fast for 19 hours. Blood donations in the past 8 weeks except for apheresis. Volunteer is having any of the following symptoms: Fever (over 100.4 oF or 38 oC) or feeling feverish New cough New shortness of breath Volunteer is having two of any of these symptoms: Chills Muscle aches New URI symptom(s) (runny nose, nasal congestion, and/or sore throat) New loss of sense of smell or sense of taste New headache Volunteer has been in close contact in the last 14 days with someone recently diagnosed with COVID-19 Volunteer has returned from international travel within the past 10 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a crossover study design. Subjects are asked to complete the study events/procedures in two phases (G.I intubation phase and SmartPill phase) with a washout period of at least 5 days between phases.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: G.I Intubation<br>Single dose of Glipizide (5 mg modified-release tablet) and Rifaximin (200 mg tablet) administered with 200 mL of 14% glucose solution in water + 1 mg of the stable isotope Glipizide (13C6-Glipizide) with 40 ml of 14% glucose solution in water. A 'Stable isotope' means a heavier version of the drug that is not radioactive. | Drug: Glucotrol XL 5Mg Extended-Release Tablet<br>* Participants are randomized to take one tablet of this study drug by mouth.<br>Drug: Glipizide ER 5 MG 24 HR Extended Release Oral Tablet<br>* Participants are randomized to take one tablet of this study drug by mouth.<br>Drug: Rifaximin 200Mg Tab<br>* Participants will take one tablet of this study drug by mouth.<br>Drug: 13C6-Glipizide<br>* Participants will take 1 mg of this study drug dissolved in 40 ml glucose solution by mouth.<br>* Other names: Stable Isotope Glipizide;|
| Experimental: SmartPill®<br>Single dose of Glipizide (5 mg modified-release tablet), Rifaximin (200 mg tablet) and SmartPill® administered with 200 mL of 14% glucose solution in water + 1 mg of the stable isotope Glipizide (13C6-Glipizide) with 40 ml of 14% glucose solution in water. | Drug: Glucotrol XL 5Mg Extended-Release Tablet<br>* Participants are randomized to take one tablet of this study drug by mouth.<br>Drug: Glipizide ER 5 MG 24 HR Extended Release Oral Tablet<br>* Participants are randomized to take one tablet of this study drug by mouth.<br>Drug: Rifaximin 200Mg Tab<br>* Participants will take one tablet of this study drug by mouth.<br>Drug: 13C6-Glipizide<br>* Participants will take 1 mg of this study drug dissolved in 40 ml glucose solution by mouth.<br>* Other names: Stable Isotope Glipizide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Area Under the Plasma Concentration-time Curve to infinite time (AUCinfinity) of Glipizide After a Single Dose of Glipizide with and without Gastrointestinal Intubation and between Two Modified Release Glipizide formulations | Average Area Under the Plasma Concentration-time Curve to infinite time (AUCinfinity) of Glipizide will be measured at multiple timepoints over a 78 hour period at each of the two study phases | From time 0 to 78 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Cmax of Glipizide After a Single Dose of Glipizide with and without Gastrointestinal Intubation and between Two Modified Release Glipizide formulations | Peak Plasma Concentration of Glipizide (Cmax) will be measured at multiple timepoints over a 78 hour period at each of the two study phases | From time 0 to 78 hours | 
| Plasma Tmax of Glipizide After a Single Dose of Glipizide with and without Gastrointestinal Intubation and between Two Modified Release Glipizide formulations | The time it takes to reach the maximum concentration of Glipizide in Plasma (Tmax) will be measured at multiple timepoints over a 78 hour period at each of the two study phases | From time 0 to 78 hours | 
| Urine and Feces concentrations of Glipizide After a Single Dose of Glipizide with and without Gastrointestinal Intubation and between Two Modified Release Glipizide formulations | Recovery of Glipizide in urine and feces will be measured at multiple timepoints over a 78 hour period at each of the two study phases | From time 0 to 78 hours | 
| Maximum Gastrointestinal fluid concentration of Glipizide after Oral Administration of a Single Dose Modified Released Formulation of Glipizide | The concentration of Glipizide in gastrointestinal fluid (stomach, duodenum, jejunum and ileum) will be measured at multiple timepoints over a 7 hour period using a 4-port G.I Intubation Catheter | From time 0 to 7 hours | 
| Gastrointestinal pH after Oral Administration of Modified Release Formulation of Glipizide | Gastrointestinal pH will be collected using SmartPill over a duration ranging from 72 hours up to 168 hours | From time 0 to (72 up to 168) hours | 
| Gastrointestinal pressure after Oral Administration of Modified Release Formulation of Glipizide | Gastrointestinal pressure will be collected using SmartPill over a duration ranging from 72 hours up to 168 hours | From time 0 to (72 up to 168) hours | 
| Gastrointestinal temperature after Oral Administration of Modified Release Formulation of Glipizide | Gastrointestinal temperature will be collected using SmartPill over a duration ranging from 72 hours up to 168 hours | From time 0 to (72 up to 168) hours | 
| Gastric Emptying (GE) Time after Oral Administration of Modified Release Formulation of Glipizide | Gastric emptying time will be collected using SmartPill over a duration ranging from 72 hours up to 168 hours | From time 0 to (72 up to 168) hours | 
| Total Gastrointestinal Transit Time after Oral Administration of Modified Release Formulation of Glipizide | Total Gastrointestinal Transit Time will be collected using SmartPill over a duration ranging from 72 hours up to 168 hours | From time 0 to (72 up to 168) hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clinical study, Glipizide, Modified release, Pharmacokinetics, In vivo dissolution, Local gastrointestinal concentration