Drug-Drug Interaction Study With Metformin and Nizatidine
Condition: Healthy
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

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.
    

Intervention name(s): Metformin and nizatidine; Metformin
Intervention type(s): Drug; Drug
Intervention description(s): Subjects will be given a single oral dose of 850 mg of metformin and a single oral dose of 600 mg of nizatidine; Subjects will be given a single oral dose of 850 mg of metformin
Other intervention name(s): Metformin: Fortamet, Glucophage; Nizatidine: Axid; GLUCOPHAGE
Intervention MeSH terms: Metformin; Nizatidine
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Drug drug interaction