Metformin Hydrochloride (Page 4 of 7)

12.3 Pharmacokinetics

Absorption

In a multiple-dose crossover study, 23 patients with type 2 diabetes mellitus were administered either metformin hydrochloride extended-release tablets 2,000 mg once a day (after dinner) or metformin HCl tablets 1,000 mg twice a day (after breakfast and after dinner). After 4 weeks of treatment, steady-state pharmacokinetic parameters, area under the concentration-time curve (AUC), time to peak plasma concentration (T max ), and maximum concentration (C max ) were evaluated. The appearance of metformin in plasma from metformin hydrochloride extended-release tablets is slower and more prolonged compared to metformin HCl tablets. Results are presented in Table 3.

Table 3 Metformin Hydrochloride Extended-Release Tablets vs. Metformin HCl Tablets Steady-State Pharmacokinetic Parameters at 4 Weeks
Pharmacokinetic Parameters (mean ± SD) Metformin Hydrochloride Extended-Release Tablets 2,000 mg (administered q.d. after dinner) Metformin HCl tablets* 2,000 mg (1,000 mg b.i.d.)
AUC 0-24hr (ng•hr/mL) 26,811 ± 7055 27,371 ± 5,781
T max (hr) 6 (3-10) 3 (1-8)
C max (ng/mL) 2849 ± 797 1820 ± 370

*Immediate-release metformin HCl tablets

In four single-dose studies and one multiple-dose study, the bioavailability of metformin hydrochloride extended-release tablets 2,000 mg given once daily, in the evening, under fed conditions [as measured by AUC] was similar to the same total daily dose administered as metformin HCl tablets 1,000 mg given twice daily. The geometric mean ratios (metformin hydrochloride extended-release tablets / metformin HCL tablets) of AUC 0-24hr , AUC 0-72hr , and AUC 0-inf for these five studies ranged from 0.96 to 1.08.

In a single-dose, four-period replicate crossover design study, comparing two 500 mg metformin hydrochloride extended-release tablets to one 1,000 mg metformin hydrochloride extended-release tablet administered in the evening with food to 29 healthy male subjects, two 500 mg metformin hydrochloride extended-release tablets were found to be equivalent to one 1,000 mg metformin hydrochloride extended-release tablet.

In a study carried out with metformin hydrochloride extended-release tablets, there was a dose-associated increase in metformin exposure over 24 hours following oral administration of 1,000, 1,500, 2,000, and 2,500 mg.

In three studies with metformin hydrochloride extended-release tablets using different treatment regimens (2,000 mg after dinner; 1,000 mg after breakfast and after dinner; and 2,500 mg after dinner), the pharmacokinetics of metformin as measured by AUC appeared linear following multiple-dose administration.

Effect of food: The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets increased by approximately 60% when given with food. When metformin hydrochloride extended-release tablets were administered with food, C max was increased by approximately 30% and T max was more prolonged compared with the fasting state (6.1 versus 4.0 hours).

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl tablets 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 4) [ See Dosage and Administration (2.2), Contraindications (4), and 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 HCl tablets 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 HCl Tablets

Subject Groups: Metformin HCl 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) 1.03 (±0.33) 2.75 (±0.81) 600 (±132)
850 mg single dose (74) d 1.60 (±0.38) 2.64 (±0.82) 552 (±139)
850 mg three times daily for 19 doses e (9) 2.01 (±0.42) 1.79 (±0.94) 642 (±173)
Adults with type 2 diabetes mellitus:
850 mg single dose (23) 1.48 (±0.5) 3.32 (±1.08) 491 (±138)
850 mg three times daily for 19 doses e (9) 1.90 (±0.62) 2.01 (±1.22) 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 (CLcr g 61 to 90 mL/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122)
Moderate (CLcr 31 to 60 mL/min) (4) 4.12(±1.83) 3.75 (±0.50) 108 (±57)
Severe (CLcr 10 to 30 mL/min) (6) 3.93 (±0.92) 4.01 (±1.10) 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 CLcr = creatinine clearance normalized to body surface area of 1.73 m 2

Pediatrics


There are no available pharmacokinetic data with metformin hydrochloride extended-Release tablets in pediatric patients.


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 Coadministered Drug on Plasma Metformin Systemic Exposure

Coadministered Drug Dose of Coadministered Drug* Dose of Metformin HCl* Geometric Mean Ratio (ratio with/without coadministered 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 HCl and coadministered 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 Coadministered Drug Systemic Exposure

Coadministered Drug Dose of Coadministered Drug* Dose of Metformin HCl* 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 HCl and coadministered 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

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2023. All Rights Reserved.