Metformin Hydrochloride (Page 4 of 7)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, 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. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

12.3 Pharmacokinetics

Absorption

The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride 500 mg to 1,500 mg and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of metformin hydrochloride, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL.

Following a single oral dose of metformin hydrochloride extended-release tablets, C max is achieved with a median value of 7 hours and a range of 4 to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride tablets, however, the extent of absorption (as measured by AUC) is comparable to metformin hydrochloride tablets.

At steady-state, the AUC and C max are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 mg to 2,000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4 and 1.8 mcg/mL for 500, 1,000, 1,500, and 2,000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets at a 2,000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1,000 mg twice daily. After repeated administration of metformin hydrochloride extended-release tablets, metformin did not accumulate in plasma.

Effect of food: Food decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (T max ) following administration of a single 850 mg tablet of metformin hydrochloride with food, compared to the same tablet strength administered fasting.

Although the extent of metformin absorption (as measured by AUC) from the metformin hydrochloride extended-release tablets increased by approximately 50% when given with food, there was no effect of food on C max and T max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended-release tablets.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

Metabolism

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.

Elimination

Renal clearance (see Table 4) 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.

Specific Populations

Renal Impairment

In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 3) [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Hepatic Impairment

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

Geriatrics

Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 4) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)] .

Table 4: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride

Subject Groups: Metformin Hydrochloride dose a

(number of subjects)

C max b

(mcg/mL)

T max c

(hrs)

Renal Clearance

(mL/min)

Healthy, nondiabetic adults:

500 mg single dose (24)

850 mg single dose (74) d

850 mg three times daily for 19 doses e (9)

1.03 (±0.33)

1.60 (±0.38)

2.01 (±0.42)

2.75 (±0.81)

2.64 (±0.82)

1.79 (±0.94)

600 (±132)

552 (±139)

642 (±173)

Adults with type 2 diabetes mellitus:

850 mg single dose (23)

850 mg three times daily for 19 doses e (9)

1.48 (±0.5)

1.90 (±0.62)

3.32 (±1.08)

2.01 (±1.22)

491 (±138)

550 (±160)

Elderly f , healthy nondiabetic adults:

850 mg single dose (12)

2.45 (±0.70)

2.71 (±1.05)

412 (±98)

Renal-impaired adults:

850 mg single dose

Mild (CL cr g 61 to 90 mL/min) (5)

Moderate (CL cr 31 to 60 mL/min) (4)

Severe (CL cr 10 to 30 mL/min) (6)

1.86 (±0.52)

4.12 (±1.83)

3.93 (±0.92)

3.20 (±0.45)

3.75 (±0.50)

4.01 (±1.10)

384 (±122)

108 (±57)

130 (±90)

a All doses given fasting except the first 18 doses of the multiple dose studies

b Peak plasma concentration

c Time to peak plasma concentration

d Combined results (average means) of five studies: mean age 32 years (range 23 to 59 years)

e Kinetic study done following dose 19, given fasting

f Elderly subjects, mean age 71 years (range 65 to 81 years)

g CL cr = creatinine clearance normalized to body surface area of 1.73 m 2

Pediatrics

After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin C max and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.

Gender

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16).

Race

No studies of metformin pharmacokinetic parameters according to race have been performed.

Drug Interactions

In Vivo Assessment of Drug Interactions

Table 5: Effect of Co-administered Drug on Plasma Metformin Systemic Exposure

Co-administered Drug

Dose of Co-administered Drug *

Dose of Metformin *

Geometric Mean Ratio (ratio with/without co-administered drug) No Effect = 1.00

AUC

C max

No dosing adjustments required for the following:

Glyburide

5 mg

850 mg

metformin

0.91

0.93

Furosemide

40 mg

850 mg

metformin

1.09

1.22

Nifedipine

10 mg

850 mg

metformin

1.16

1.21

Propranolol

40 mg

850 mg

metformin

0.90

0.94

Ibuprofen

400 mg

850 mg

metformin

1.05

1.07

Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [see Warnings and Precautions (5.1) and Drug Interactions (7)].

Cimetidine

400 mg

850 mg

metformin

1.40

1.61

Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5.1) and Drug Interactions (7)].

Topiramate

100 mg §

500 mg §

metformin

1.25 §

1.17

* All metformin and co-administered drugs were given as single-doses

AUC = AUC(INF)

Ratio of arithmetic means

§ At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h

Table 6: Effect of Metformin on Co-administered Drug Systemic Exposure

Co-administered

Drug

Dose of

Co-administered Drug *

Dose of

Metformin *

Geometric Mean Ratio

(ratio with/without metformin)

No Effect = 1.00

AUC

C max

No dosing adjustments required for the following:

Glyburide

5 mg

850 mg

glyburide

0.78

0.63

Furosemide

40 mg

850 mg

furosemide

0.87

0.69

Nifedipine

10 mg

850 mg

nifedipine

1.10 §

1.08

Propranolol

40 mg

850 mg

propranolol

1.01 §

1.02

Ibuprofen

400 mg

850 mg

ibuprofen

0.97

1.01

Cimetidine

400 mg

850 mg

cimetidine

0.95 §

1.01

* All metformin and co-administered drugs were given as single-doses

AUC = AUC(INF) unless otherwise noted

Ratio of arithmetic means, p-value of difference < 0.05

§ AUC (0-24 hr) reported

Ratio of arithmetic means

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