12. CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Metformin is a biguanide that improves glucose tolerance in patients with type2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in patients with type2 diabetes or in healthy subjects except in special circumstances, (see WARNINGS AND PRECAUTIONS (5)) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.

12.3 Pharmacokinetics
Absorption and Bioavailability

Following a single oral dose of 1000mg (2x 500mg 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 (2x 500mg 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.

Single oral doses of GLUMETZA from 500mg to 2500mg resulted in less than proportional increase in both AUC and Cmax. 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.

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 doses.

Metabolism

Intravenous single-dose studies in healthy 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. Metabolism studies with extended-release metformin tablets have not been conducted.

Excretion

Renal clearance is approximately 3.5times 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 24hours, with a plasma elimination half-life of approximately 6.2hours. In blood, the elimination half-life is approximately 17.6hours, suggesting that the erythrocyte mass may be a compartmen