crossover study to evaluate the comparative bioavailability of two fixed dose combination tablet formulations of extended release metformin and extended release glimepiride in health volunteers

Conditions: Diabetes Mellitus, Type 2

Summary: this is a an open-label, randomized, single dose, four-way crossover, multi-stage study enrolling 20 healthy adult male and female subjects per part. this study consists of two separate parts (part a and b) with each part comprising four treatment periods. each subject will participate in all four treatment periods per part; subjects may not enrol in both parts a and b. this study is being conducted to compare the pharmacokinetics (pk) of two extended release fixed dose combinations (fdc) oral formulations of metformin and glimepiride at two doses, 500mg/1mg and 1000mg/2mg, with each fdc formulation to be administered orally as a single dose and compared with the commercially available formulations of metformin extended release (xr) (glucophage ™ sustained release \[sr\]) and glimepiride immediate release (ir) (amaryl ™). part a of study will evaluate the bioavailability of a formulation comprising a film coated tablet containing release controlling polymers; and part b will evaluate the bioavailability of a formulation comprising a tablet coated with release controlling polymers. in each part there will be 4 treatment periods. during each period, subjects will be randomized sequentially to receive a single dose of a reference treatment of 500 mg metformin xr / 1 mg glimepiride ir; and a reference treatment of 1000 mg metformin xr / 2 mg glimepiride ir; and an fdc tablet containing 500 mg metformin xr and 1 mg glimepiride xr; and an fdc tablet containing 1000 mg metformin xr and 2 mg glimepiride xr.serial pk sampling for up to 36 hours and safety assessments will be performed. each period will be separated by a washout period of at least 5 days and a follow-up visit will occur 14 days after the last dose of study drug.


Eligibility criteria:
inclusion criteria: * healthy male or female subjects between 18 and 65 years of age inclusive with body weight \>= 50 kg and body mass index (bmi) within the range 19 to 32 kilogram/meter squared * alanine aminotransferase (alt) alkaline phosphatase and bilirubin \<or=1.5x upper limit of normal (uln). * normal ecg measurements. average qt duration corrected for heart rate by fridericia's formula (qtcf) \<450 millisecond or qtcf \<480 msec in subjects with bundle branch block based on an average from three electrocardiograms (ecgs) obtained over a brief recording period. * female subjects of non-child bearing potential. females of child bearing potential are eligible to enter if they are not pregnant and willing to use protocol-specified methods of contraception to prevent pregnancy until 14 days post-last dose of metformin/glimepiride. * capable of giving written informed consent exclusion criteria: * the subject has a positive: drug/alcohol screen, hepatitis, hiv screen * abuse of alcohol * current or chronic history of liver disease, or known hepatic or biliary abnormalities * exposure to more than four new investigational chemical entities within 12 months prior to the first dosing day * participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) * sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or gsk medical monitor, contraindicates their participation * donation of more than 500 ml blood within a 56 day period * pregnant or lactating females * unwillingness or inability to follow the procedures outlined in the protocol * subject is mentally or legally incapacitated * subject having positive urinary cotinine levels indicative of use of tobacco or nicotine-containing products within 6 months prior to screening. * unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose * subjects having asthma or are positive carbon monoxide (co) on admission to the unit * unable to refrain from the use of prescription or non-prescription drugs within 7 days prior to first dose of study medication, unless approved by the investigator and gsk medical monitor.

Keywords: healthy volunteers diabetes mellitus glimepiride pharmacokinetics metformin