Pharmacokinetics
Absorption and Bioavailability

The following pharmacokinetic studies were performed with the 500mg dosage form.

Following a single oral dose of 1000mg (2x500mg tablets) GLUMETZA after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7-8hours. In both single and multiple-dose studies in healthy subjects, once daily 1000mg (2x500mg tablets) dosing provides equivalent systemic exposure, as measured by area-under-the-curve (AUC), and up to 35% higher Cmax, of metformin relative to the immediate release given as 500mg twice daily. GLUMETZA tablets must be administered immediately after a meal to maximize therapeutic benefit.

Table 1: Summary Mean (±SD) of Pharmacokinetic Parameters after One Day Dosing  PK Parameter  Glumetza
2x500mg  Glumetza
1x500mg BID  Glucophage
1x500mg 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 

Single oral doses of GLUMETZA from 500mg to 2500mg resulted in less than proportional increase in both AUC and Cmax. The mean Cmax values were 473 ±145, 868 ±223, 1171 ±297, and 1630 ±399ng/mL for single doses of 500, 1000, 1500, and 2500mg, respectively. For AUC, the mean values were 3501 ±796, 6705 ±1918, 9299 ±2833, and 14161 ±4432ng•hr/mL for single doses of 500, 1000, 1500, and 2500mg, respectively.

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 Tmax by approximately 3hours but Cmax was not affected.

In a two-way, single-dose crossover study in healthy volunteers, the 1000mg tablet was found to be bioequivalent to two 500mg tablets under fed conditions based on equivalent Cmax and AUCs for the two formulations (Table2).

Table 2: Mean (±SD) Pharmacokinetic Parameters for Glumetza 1000mg Tablet and Glumetza 2x500mg Tablets  PK Parameters  Glumetza
1000mg Tablet  Glumetza
2x500mg 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 850mg immediate release metformin hydrochloride averaged 654 ±358L. 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 24-48hours and are generally < 1μg/mL. During controlled clinical trials, which served as the basis of approval for metformin, maximum metformin plasma levels did not exceed 5μg/mL, even at maximum dose