Evaluation of Food Effect on the Pharmacokinetics of Sustained Release Metformin in Healthy Indian Volunteers
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      Metformin hydrochloride in its immediate release (IR) form has been successfully used for
      decades in the treatment of type 2 diabetes; however the IR formulation may be associated
      with gastrointestinal side effects (especially nausea, diarrhea) in 20-30% patients, which
      can limit the tolerated dose, reduce adherence and result in discontinuation of therapy.
      Metformin hydrochloride extended release formulations have been developed to overcome these
      problems. In India, extended release formulations of metformin hydrochloride include
      metformin SR 1000mg tablet and combination of metformin hydrochloride SR 1000mg/glimepiride
      2mg tablet. In the combination tablet, only metformin hydrochloride is in the extended
      release form. In view of the fact that extended release metformin hydrochloride is usually
      recommended with a meal, that food is known to affect the pharmacokinetic (PK) parameters of
      metformin and that there is a potential for dose dumping with extended release formulations
      that may lead to side effects similar to IR formulations, a study to estimate the magnitude
      of the food effect for these formulations in fed state compared to the fasting state is
      warranted. This study will be a randomized, single-center, open-label, single-dose,
      three-period, 6 sequence crossover study in 30 healthy adult volunteers to estimate the
      bioavailability of metformin from metformin hydrochloride 1000mg SR tablet given in fasting
      condition relative to metformin hydrochloride 1000mg SR tablet and a fixed dose combination
      of metformin hydrochloride 1000mg SR /glimepiride 2mg tablet, each given in fed condition.
      The safety and tolerability profile of metformin SR 1000mg tablet and metformin hydrochloride
      SR 1000mg/glimepiride 2mg tablet will also be evaluated in this study. The primary PK
      endpoints will be Cmax and AUC (0-∞). The secondary PK endpoints will include AUC (0-t), Tmax
      , T lag, Kel and t1/2. Safety endpoints will include vital signs, ECG, physical examination,
      clinical laboratory tests and adverse event reporting.
    

Detailed description: 
      Background:

      Metformin hydrochloride, a biguanide, is an effective treatment for type 2 diabetes, lowering
      both basal and postprandial hyperglycemia either as monotherapy or in combination with other
      antihyperglycemic drugs. Metformin hydrochloride in its immediate release form (IR) has been
      used for decades in the treatment of type 2 diabetes. An IR formulation releases the entire
      drug within 1-2 h after dosing, resulting in high drug concentrations in the GI
      (gastrointestinal) tract which may be associated with GI side effects (especially nausea,
      diarrhea) in 20-30% patients. This can limit the tolerated dose, reduce adherence and result
      in discontinuation of therapy. In addition, the frequent need to administer metformin two or
      three times daily may also not support good adherence to therapy.

      Metformin hydrochloride extended release (ER) formulations have been developed to overcome
      these problems. Because metformin gets absorbed in the first part of the small intestine,
      extended release metformin hydrochloride formulations employ various novel gastric-retentive
      techniques. The polymeric matrix (hydroxyl propyl methyl cellulose) of the extended release
      metformin tablet is designed to swell in the gastric fluid. As the matrix swells, it becomes
      resistant to peristalsis and is more easily retained in the stomach. Gastric fluid penetrates
      the matrix, dissolving the drug which then diffuses out of the matrix in the liquefied form.
      Metformin hydrochloride is thus slowly released from the matrix of the tablet and is absorbed
      when this gastric fluid passes through the small intestine. The slow release of the drug in
      the GI tract permits once daily dosing and also reduces the incidence of nausea (6.5%) and
      diarrhea (9.6%). These factors are particularly relevant for increasing treatment adherence
      to long term therapies like anti-diabetic medication.

      Glimepiride, a new generation sulphonylurea, in doses of 1-8mg/day, is an effective treatment
      option for non-insulin dependent diabetes mellitus (NIDDM) patients. Oral bioavailability is
      approximately 100% and the absence of a food interaction guarantees highly reproducible
      pharmacokinetics with this drug. A combination tablet formulation of sustained release
      metformin hydrochloride and glimepiride is beneficial in terms of convenience of
      administration and patient compliance.

      Metformin hydrochloride extended-release formulation should generally be given once daily
      with the evening meal. Administration with food increases the bioavailability of metformin
      hydrochloride. Food increases the extent of absorption (AUC) of metformin hydrochloride (AUC
      13306 ng h/ml with high fat breakfast, AUC 10200 ng h/ml with a low fat breakfast, AUC 7506
      ng h/ml in fasting condition). Food can either cause no change or an increase in Cmax of the
      drug. One study has reported no effect of food on the Cmax of metformin [high fat meal (1018
      ng/ml), low fat meal (992 ng/ml) and fasting condition (1022 ng/ml)]. In contrast, in a
      healthy volunteer study with Glucophage SR 1000mg, food increased the extent of absorption
      (AUC) by 77%, peak plasma concentration (Cmax) by 26% and prolonged time to peak plasma
      concentration (Tmax) by about 1 hour as compared to the fasting state.

      The mechanical stress of the grinding action of the stomach in the fed state could introduce
      variability if an extended release tablet containing metformin hydrochloride is broken down
      more rapidly than anticipated. Because food prolongs the gastric retention time, extended
      release formulations administered with food are exposed to longer duration of mechanical
      stress in the stomach. The latter raises the possibility of increased release rate (than
      intended) of the drug from the formulation. This can result in a higher risk of 'dose
      dumping', creating a potential safety risk for patients. Therefore it is clinically important
      to assess the effect of food on extended release formulations of metformin hydrochloride and
      metformin hydrochloride/glimepiride.

      Study Rationale:

      Extended release formulations of metformin hydrochloride in India include metformin SR 1000mg
      tablet and metformin hydrochloride SR 1000mg/glimepiride 2mg tablet. In the combination
      tablet, only metformin hydrochloride is in the extended release form. In view of the fact
      that extended release metformin hydrochloride is usually recommended with a meal, that food
      is known to affect the PK parameters of metformin and that there is a potential for dose
      dumping with extended release formulations that may lead to side effects similar to IR
      formulations, a study to estimate the magnitude of the food effect for these formulations in
      fed state compared to the fasting state is warranted. The safety and tolerability profile of
      metformin SR 1000mg tablet and metformin hydrochloride SR 1000mg/glimepiride 2mg tablet will
      also be evaluated in this study.

      Objectives:

      Primary:

      To compare the pharmacokinetics and bioavailability of metformin given in a fed condition
      either as metformin hydrochloride 1000mg SR tablet or as a fixed dose combination of
      metformin hydrochloride 1000mg SR/glimepiride 2mg tablet with that given in fasting condition
      as metformin hydrochloride 1000mg SR tablet in healthy Indian volunteers.

      Secondary:

      To compare the safety and tolerability of metformin hydrochloride given in a fed condition
      either as metformin hydrochloride 1000mg SR tablet or as a fixed dose combination of
      metformin hydrochloride 1000mg SR/glimepiride 2mg tablet with that given in fasting condition
      as metformin hydrochloride 1000mg SR tablet in healthy Indian volunteers.

      Study Design/Schematic:

      This study will be a randomized, single-center, open-label, single-dose, three-period, 6
      sequence crossover study in healthy adult volunteers to estimate the bioavailability of
      metformin from metformin hydrochloride 1000mg SR tablet given in fasting condition relative
      to metformin hydrochloride 1000mg SR tablet and a fixed dose combination of metformin
      hydrochloride 1000mg SR /glimepiride 2mg tablet, each given in fed condition.

      30 healthy adult males will be randomized to receive a single dose of metformin hydrochloride
      SR (1000mg) in fasting state or metformin hydrochloride SR (1000mg) in fed state or a fixed
      dose combination of metformin hydrochloride 1000mg SR /glimepiride 2mg tablet in fed state in
      each treatment period. There will be 6 treatment sequences and a washout of 7 days between
      each of the three treatment periods.

      Subjects will have a screening visit within 21 days prior to the first dose of study drug,
      followed by three treatment periods, each containing a single dose of study drug, followed by
      30 hours of serial PK sample collection. Subjects will check out of the unit on Day +1 after
      collection of the 30 hour PK sample. Subjects will be instructed to return for the next
      treatment period or for the final follow-up visit, as appropriate. The final follow-up visit
      will occur 7 days after the last dose of study drug. Subjects will be assigned to each of the
      three treatments randomly as per the randomization schedule.

      Study participants will check into the study unit of the clinical research organisation at
      least 12 hours prior to dosing and will remain in the clinical research unit up to 36 hours
      after the administration of the investigational product. In the fasting and fed conditions,
      the pre-dose dinner will be administered 11 hours prior to dosing of the drug.

      Following a 10-hour overnight fast, subjects will be randomized as per predetermined
      randomization sequences to any of three study treatment arms in a ratio of 1:1:1 and then
      administered a single oral dose of study drug (A: metformin SR 1000 mg in fasting state, B:
      metformin SR 1000 mg in fed state, C: metformin SR 1000 mg/glimepiride 2 mg in fed state) in
      treatment period 1. In the subsequent two study periods, subjects will receive the other
      treatments, according to the randomisation schedule so that all subjects receive all
      treatments.

      In the fasting condition, the dosing of the drug will take place at the scheduled time
      followed by breakfast, lunch and dinner at 4, 8 and 13 hours post dose respectively. On D+1
      (day after the dosing day), breakfast and lunch will be provided at 25 hours and 30 hours
      post dose respectively.

      In the fed condition, breakfast will be served at the scheduled time. The dosing of drug will
      be at the same scheduled time as dosing in the fasting condition. Lunch, snack and dinner
      will be served at 4, 9 and 13 hours post dose respectively. On D+1, breakfast and lunch will
      be provided at 25 hours and 30 hours post dose respectively.

      According to CDSCO recommendations for high-fat breakfast for BA/BE fed state studies,
      participants must consume the high-fat breakfast (950-1000 kcal, at least 50% of calories
      from fat, 15-20% from protein and the rest from carbohydrates) approximately 15minutes prior
      to dosing. A random high fat breakfast sample served in the study will be sent for analysis
      and the caloric breakdown of the test meal will be calculated. In both, fasting and fed
      conditions, the study medication will be administered with 240 ml of a 20% glucose solution.
      Thereafter, 60 ml of a 20% glucose solution will be administered every 15 minutes for up to 4
      hours after dosing.

      In each period, a total of 18 blood samples will be collected using pre-labelled 6ml K3EDTA
      vacutainers as per the following schedule: 0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5,
      5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing. The volunteers will be housed for 36
      hours after dosing. The bioanalyst will be blinded to study treatments received by the
      subject.
    

Intervention name(s): Metformin hydrochloride prolonged release; metformin hydrochloride prolonged release; Metformin hydrochloride sustained release/Glimepiride
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 1000mg in fasting state; 1000mg in fed state; 1000/2mg in fed state
Intervention MeSH terms: Metformin; Glimepiride
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Other