Drug-Drug Interaction Study With Metformin and Nizatidine

April 9, 2014 updated by: University of California, San Francisco

The Pharmacokinetic Interaction Between Metformin and Nizatidine in Healthy Volunteers

This study will address the following question: Does nizatidine affect the pharmacokinetics of metformin in healthy volunteers? Recent studies in the Giacomini laboratory have indicated that nizatidine may block metformin elimination from the kidney by inhibiting organic cation transporter efflux of metformin. The investigators hypothesize that the co-administration of metformin and nizatidine will reduce the renal clearance (CLR) of metformin leading to increased plasma concentrations and potential risk for toxicities. Knowledge of the pharmacokinetic interaction profile of metformin with organic transporter inhibitors, such as nizatidine, is important to help develop safer more effective drug therapy with reduced side effects.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Screening Procedures:

Prior to enrollment, subjects will be asked to come to the Clinical and Translational Science (CTSI) Clinical Research Centre (CRC) at San Francisco General Hospital (SFGH). The study protocol and procedures will be explained in detail, all questions will be answered, and subjects will be provided a consent form to sign. The screening visit will be conducted within 14 days of the first inpatient visit i.e. first metformin alone or metformin with nizatidine dosing day.

Only after subjects have consented to participate in the study will the screening procedures commence. All subjects recruited in this study will have already consented to the pharmacogenomics in ethnically diverse populations (SOPHIE) study, a previously established cohort of healthy people living in San Francisco. A review of the subject's medical history and health questionnaire will be conducted to re-assess health status and confirm eligibility (see attached health questionnaire). Changes in medication or drug use history will be noted during the study.

During the screening visit, vital signs as well as blood and urine samples will be taken from all subjects for laboratory analysis. A single blood sample (10 mL) will be taken by venipuncture to measure a complete blood count (CBC), electrolytes, blood urea nitrogen (BUN), creatinine, and liver function tests (LFTs) to screen for anemia and renal or hepatic insufficiency (see Inclusion/Exclusion Criteria).

Procedures During Main Study:

An equal number of subjects will be randomized, by a computer program, into one of the two study arms described below, prior to their screening visit. After at least a 1-week washout period, subjects will be assigned to the other treatment arm. The duration of the study will consist of two 24-hour inpatient study visits (2 non-consecutive overnight stays), separated by at least 1-week wash out period.

Randomized Study Visit Day 1: Metformin alone Subjects will report to the CRC at approximately 7:30 AM, after an overnight fast of at least 10 hours (fasted from approximately 10:00 PM). Vital signs and a brief history will be taken upon arrival. If all inclusion/exclusion criteria are met, one intravenous (IV) catheter will be inserted into a forearm vein to facilitate blood sampling. An initial blood sample of 10 mL will be drawn (from the IV line) for the determination of plasma metformin, creatinine, and nizatidine concentrations prior to the administration of metformin (i.e. baseline measurement). Next, each subject will receive an oral dose of 850 mg of metformin with 8 oz of water. Blood samples (5 mL each) will then be drawn at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours post-dose for the determination of plasma metformin and nizatidine concentrations. An additional 5 mL of blood will be drawn at the 6-hour and 12-hour time points for the measurement of serum creatinine to allow the calculation of creatinine clearance (CLcr). Blood samples obtained by finger prick will be taken at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours after ingestion of metformin (total of 0.1 mL) to measure blood glucose levels. Additional biomarkers of metformin/nizatidine response and toxicities, such as plasma insulin, glucose and AMPK activation, may also be determined on the blood samples collected. Subjects will remain at the CRC and receive standardized meals starting 4 hours post metformin dosing. Subjects will be discharged and allowed to go home the following morning after the collection of the last (24 hour) blood and urine sample at approximately 8 AM. All blood samples will be centrifuged, and the plasma separated immediately and stored at -80oC until analysis.

Urine collection:Subjects will be asked to void their bladder prior to metformin administration (baseline urine sample) and to drink 8 oz of water every 4 hours to maintain urine flow and pH. Aliquots of urine will be collected for the following time frames: 0-2, 2-4, 4-8, 8-12, and 12-24 hours post metformin dosing. Additionally, aliquots from collections taken between 0-12 and 0-24 hours will be pooled for analysis of creatinine. Subjects will be advised to collect all urine produced during the inpatient visit. The volume and pH of each urine collection will be recorded and an aliquot (20 mL) from each collection period will be stored at -80°C for determination of urinary metformin, creatinine, nizatidine and nizatidine metabolite concentrations.

Randomized Study Visit Day 2:Co-administration of metformin with nizatidine Subjects will report to the CRC after an overnight fast as previously described. After the collection of the baseline blood and urine samples, subjects will receive an oral dose of 600 mg nizatidine and 850 mg of metformin with 8 oz of water. The study procedures described in "Randomized Study Visit Day 1" and "Urine collection" will be repeated.

Study Restrictions:

Concomitant Medications:

The study requires that healthy participants refrain from taking any medications (except for daily vitamins or oral contraceptives) for the duration of the study, in particular medication(s) that interfere with the pharmacokinetics of metformin or nizatidine (See Exclusion criteria 13.7).

Other Study Restrictions:

Subjects will be required to use adequate contraceptive means to avoid pregnancy throughout the study. Subjects must remain within the CRC throughout the two 24 hour inpatient visits unless accompanied by a CRC staff member. Subjects are to refrain from smoking and from ingesting caffeine, alcohol, orange and grapefruit juice containing products from the night before each inpatient study day until the study is complete, approximately 24 hours after dosing.

Clinical and Laboratory Determinations:

Analytical Methods:

Measurement of metformin, creatinine, nizatidine and nizatidine metabolites in plasma and urine will be preformed by High Performance Liquid Chromatography (HPLC) with tandem mass spectrometry (MS/MS), using assays previously described and validated20-22.

Hematology, Blood Chemistry and Urinalysis:

The following standard biochemistry, blood chemistry and urinalysis will be performed at the screening visit:

  1. Hematology, (Complete Blood Count with differential, CDP): WBC with differential, red blood cells (RBC), RBC indices (HGB, HCT, MCV, MCH, MCHC) and platelet count.
  2. Blood chemistry (Metabolic Comprehensive Panel, METC): sodium, potassium, chloride, carbon dioxide, creatinine, blood urea nitrogen, glucose, calcium, bilirubin (total), phosphate (total), AST, ALT, albumin and alkaline phosphatase
  3. Urinalysis: urine protein (dipstick) and blood (dipstick).

Other: Pregnancy test:

A urine test will be administered to females who have had their first menstrual period to make ensure that they are not pregnant. Pregnant females will be excluded from the study.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
10

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94158
        • Ucsf Ctsi Crc

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 45 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Age 18-45 years
  2. Male or female
  3. If female, using appropriate contraception
  4. Healthy as judged by medical examination, medical history and normal biochemical and hematological measures
  5. Normal urinalysis and renal function
  6. Understand the nature and purpose of the study and provide informed consent

Exclusion Criteria:

  1. Pregnant or lactating woman (female subjects will have a urine pregnancy test at the screening visit)
  2. Abnormal bone marrow function (leukocyte, neutrophil, or platelet counts outside the normal range)
  3. History of hypersensitivity or allergic reaction to metformin or nizatidine
  4. Risk of congestive heart failure requiring pharmacologic treatment (medical history)
  5. History of renal or hepatic dysfunction (e.g., CLcr <60mL/min, ALT >80U/L, AST>60 U/L)
  6. Anemic (hemoglobin <12 g/dL)
  7. Use of any medications (including over the counter products, herbal products, or mineral supplements) with the exception of a daily vitamin or oral contraceptives. In particular use of medications that are known to interfere with the pharmacokinetics of metformin and nizatidine such as cimetidine, cetirizine, ketoconazole, procainamide, St. John's Wort, and testosterone are prohibited.
  8. Laboratory parameters that are more than 2 standard deviations from the laboratory mean
  9. Subject carries a MATE2K gene variant that is predicted to effect MATE2K protein expression

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Metformin
Subjects will be dosed with Metformin alone (850 mg)
Drug: Metformin
Subjects will be given a single oral dose of 850 mg of metformin
Other Names:
  • GLUCOPHAGE
EXPERIMENTAL: Metformin and Nizatidine
Subjects will be dosed with metformin in conjunction with nizatidine
Drug: Metformin and nizatidine
Subjects will be given a single oral dose of 850 mg of metformin and a single oral dose of 600 mg of nizatidine
Other Names:
  • Metformin: Fortamet, Glucophage
  • Nizatidine: Axid

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Composite of Pharmacokinetics of co-administration of nizatidine & metformin in healthy volunteers.
Time Frame: 24 hours
Cmax and Tmax will be determined from AUC-time curve Glomerular filtration rate (GFR) will be approximated by measured creatinine clearance using the following equation:GFR calculation: GFR = CLcreatinine = (Urinary creatinine * V) / (Plasma creatinine)
24 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of California, San Francisco

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of General Medical Sciences (NIGMS)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Kathleen M Giacomini, Ph.D, University of California, San Francisco

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 1, 2011

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 1, 2013

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 1, 2013

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 29, 2011

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 2, 2011

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 4, 2011

Study Record Updates

Last Update Posted (ESTIMATE)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 10, 2014

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 9, 2014

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 6968
  • R01GM036780 (NIH)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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