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

Summary: 
      This study will address the following question: Does imatinib influence the pharmacokinetics
      of metformin in healthy volunteers? Recent studies in the Giacomini laboratory have indicated
      that imatinib may block metformin elimination from the kidney by inhibiting organic cation
      transporter efflux of metformin. 1. The investigators hypothesize that the addition of
      imatinib to metformin therapy will reduce the renal clearance (CLR) of metformin leading to
      increased plasma concentrations and risk for toxicities 2. Knowledge of the pharmacokinetic
      interaction profile of metformin with organic cation transporter inhibitors, such as
      imatinib, 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 must be conducted
      within 14 days of the first inpatient visit i.e. first metformin alone or metformin and
      imatinib 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, by the research staff, to re-assess health status
      and confirm eligibility. Changes in medical 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).

      After their screening visit, an equal number of subjects will be randomized, by a random
      number generator in excel, into one of the two study arms; metformin alone followed by the
      co-administration of metformin and imatinib.

      Procedures During Main Study:

      Randomized Study Visit Arm 1: Metformin alone Subjects will report to the CRC at
      approximately 7:30 AM, after an overnight fast of at least 10 hours (since 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 imatinib
      concentrations prior to the administration of metformin (i.e. baseline measurement). Next
      each subject will receive an oral dose of 1000 mg of metformin with 8 oz of water followed by
      an oral dose of 850mg. 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
      imatinib 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/imatinib 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 for the 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 and creatinine
      concentrations.

      Randomized Study Visit Day 2:Co-administration of metformin with imatinib Subjects will
      present 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 imatinib
      and 1000 mg of metformin with 8 oz of water followed by an oral dose of 850mg. 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 imatinib (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:

      Measurement of metformin, creatinine, imatinib and CGP74588 in plasma and urine will be
      preformed by High Performance Liquid Chromatography (HPLC) with tandem mass spectrometry
      (MS/MS) using assays previously described and validated.

      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).
    

Intervention name(s): Metformin; Imatinib
Intervention type(s): Drug; Drug
Intervention description(s): Subjects will be given an oral dose of 1000 mg of metformin followed by an oral dose of 850 mg for a grand total of 1850 mg in both study Arm 1 and study Arm 2.; A single oral dose of 600 mg of imatinib
Other intervention name(s): GLUCOPHAGE; GLEEVEC
Intervention MeSH terms: Metformin; Imatinib Mesylate
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Drug drug interaction