Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from GLUMETZA tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin T by approximately 3 hours but C was not affected.

In a two-way, single-dose crossover study in healthy volunteers, the 1000 mg tablet was found to be bioequivalent to two 500 mg tablets under fed conditions based on equivalent C and AUCs for the two formulations (Table 2).

Table 1: Summary Mean (±SD) of Pharmacokinetic Parameters after One Day Dosing PK Parameter Glumetza
2x500 mg Glumetza
1x500 mg BID Glucophage
1x500 mg BID
AUC0-36 (ng.hr/mL) 14182 ± 2415 15260 ± 3496 15342 ± 3398
Cmax (ng/mL) 1301.4 ± 285.7 811.9 ± 173.7 959.1 ± 204.0
Tmax (hr) 7.5 ± 1.2 7.1 ± 1.2 4.2 ± 1.6
Table 2: Mean (±SD) Pharmacokinetic Parameters for Glumetza 1000 mg Tablet and Glumetza 2x500 mg Tablets PK Parameters Glumetza
1000 mg Tablet Glumetza
2x500 mg Tablets
AUC0-t (ng.hr/mL) 11706 ± 2520 12408 ± 2581
AUC0-∞ (ng.hr/mL) 11907 ± 2521 12599 ± 2616
Cmax (ng/mL) 1238 ± 271 1116 ± 254

Distribution
The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg immediate release metformin hydrochloride averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 μg/mL. During controlled clinical trials, which served as the basis of approval for metformin, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.

Metabolism and Excretion
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans), nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations
Renal Impairment: In patients with mild and moderate renal failure (based on measured creatinine clearance) the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively (see  WARNINGS ). Metformin peak and systemic exposure were significantly greater in patients with renal failure relative to healthy volunteers with normal renal function. There was a rank-order correlation of metformin AUC and C with degree of renal failure. Since metformin can accumulate to toxic levels in patients with renal impairment, administration of GLUMETZA is contraindicated in these patients.

Hepatic Impairment: No pharmacokinetic studies of GLUMETZA have been conducted in subjects with hepatic insufficiency.

Geriatri