Prescription Drug Information: Pioglitazone Hydrochloride and Metformin Hydrochloride (Page 5 of 8)

12.3 Pharmacokinetics


Pioglitazone and Metformin Hydrochloride

In bioequivalence studies of pioglitazone and metformin hydrochloride 15 mg/500 mg and 15 mg/850 mg, the area under the curve (AUC) and maximum concentration (Cmax ) of both the pioglitazone and the metformin component following a single dose of the combination tablet were bioequivalent to pioglitazone hydrochloride 15 mg concomitantly administered with metformin hydrochloride (500 mg or 850 mg respectively) tablets under fasted conditions in healthy subjects.
Administration of pioglitazone and metformin hydrochloride 15 mg/850 mg with food resulted in no change in overall exposure of pioglitazone. With metformin there was no change in AUC; however, mean peak serum concentration of metformin was decreased by 28% when administered with food. A delayed time to peak serum concentration was observed for both components (1.9 hours for pioglitazone and 0.8 hours for metformin) under fed conditions. These changes are not likely to be clinically significant.


Following once-daily administration of pioglitazone, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within seven days. At steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state, in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC.
Cmax , AUC, and trough serum concentrations (Cmin ) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.
Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four hours, but does not alter the extent of absorption (AUC).

Metformin hydrochloride

The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets of 500 mg to 1500 mg, and 850 mg to 2550 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, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
Food decreases the rate and extent of metformin absorption, as shown by a 40% lower mean Cmax , a 25% lower AUC, and a 35-minute prolongation of Tmax following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.



The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. M-III and M-IV are also extensively bound (>98%) to serum albumin.

Metformin hydrochloride

The Vd/F of metformin following single oral doses of 850 mg immediate-release metformin averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.



Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major circulating active metabolites in humans.

In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone which include CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms, including the mainly extrahepatic CYP1A1. In vivo study of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor, showed that pioglitazone is a CYP2C8 substrate [see Dosage and Administration (2.3) and Drug Interactions (7.1)]. Urinary 6ß­-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

Metformin hydrochloride

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.

Excretion and Elimination


Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.
The mean serum half-life (t1/2 ) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be five to seven L/hr.

Metformin hydrochloride

Renal clearance is approximately 3.5 times greater than creatinine clearance (CLcr), 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 t1/2 of approximately 6.2 hours. In blood, the elimination t1/2 is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Specific Populations

Renal Impairment

The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (CLcr 30 to 50 mL/min) and severe (CLcr <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dose adjustment in patients with renal impairment is required.
Metformin hydrochloride

In patients with decreased renal function, the plasma and blood t1/2 of metformin is prolonged and the renal clearance is decreased [see Dosage and Administration (2.2), Contraindications (4) and Warnings and Precautions (5.2)].

Hepatic Impairment
Compared with healthy controls, subjects with impaired hepatic function (Child-Turcotte-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III, and M-IV) mean Cmax but no change in the mean AUC values. Therefore, no dose adjustment in patients with hepatic impairment is required.
There are postmarketing reports of liver failure with pioglitazone and clinical trials have generally excluded patients with serum ALT >2.5 times the upper limit of the reference range. Use pioglitazone and metformin hydrochloride with caution in patients with liver disease [see Warnings and Precautions (5.5)].
Metformin hydrochloride

No pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment [see Warnings and Precautions (5.5)].
Geriatric Patients

In healthy elderly subjects, Cmax of pioglitazone was not significantly different, but AUC values were approximately 21% higher than those achieved in younger subjects. The mean t1/2 of pioglitazone was also prolonged in elderly subjects (about ten hours) as compared to younger subjects (about seven hours). These changes were not of a magnitude that would be considered clinically relevant.

Metformin hydrochloride

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total CL/F is decreased, the t1/2 is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.


Safety and efficacy of pioglitazone in pediatric patients have not been established. Pioglitazone and metformin hydrochloride is not recommended for use in pediatric patients [see Use in Specific Populations (8.4)].

Metformin hydrochloride

After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin Cmax 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), and all with normal renal function.



The mean Cmax and AUC values of pioglitazone were increased 20% to 60% in women compared to men. In controlled clinical trials, HbA1c decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%). Because therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.



Pharmacokinetic data among various ethnic groups are not available.

Metformin hydrochloride

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Drug-Drug Interactions

Specific pharmacokinetic drug interaction studies with pioglitazone and metformin hydrochloride have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.


Table 17. Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs
* Daily for 7 days unless otherwise noted % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively Pioglitazone had no clinically significant effect on prothrombin time
Coadministered Drug
Pioglitazone Dosage Regimen (mg)* Name and Dose Regimens Change in AUC Change in Cmax
45 mg(N = 12) Warfarin
Daily loading then maintenance doses based PT and INR values Quick’s Value = 35 ± 5% R-Warfarin ↓3% R-Warfarin ↓2%
S-Warfarin ↓1% S-Warfarin ↑1%
45 mg(N = 12) Digoxin
0.2 mg twice daily (loading dose) then 0.25 mg daily (maintenance dose, 7 days) ↑15% ↑17%
45 mg dailyfor 21 days(N = 35) Oral Contraceptive
[Ethinyl Estradiol (EE) 0.035 mg plus Norethindrone (NE) 1 mg] for 21 days EE ↓11% EE ↓13%
NE ↑3% NE ↓7%
45 mg(N = 23) Fexofenadine
60 mg twice daily for 7 days ↑30% ↑37%
45 mg(N = 14) Glipizide
5 mg daily for 7 days ↓3% ↓8%
45 mg dailyfor 8 days(N = 16) Metformin
1000 mg single dose on Day 8 ↓3% ↓5%
45 mg(N = 21) Midazolam
7.5 mg single dose on Day 15 ↓26% ↓26%
45 mg(N = 24) Ranitidine
150 mg twice daily for 7 days ↑1% ↓1%
45 mg dailyfor 4 days(N = 24) Nifedipine ER
30 mg daily for 4 days ↓13% ↓17%
45 mg(N = 25) Atorvastatin Ca
80 mg daily for 7 days ↓14% ↓23%
45 mg(N = 22) Theophylline
400 mg twice daily for 7 days ↑2% ↑5%
Table 18. Effect of Coadministered Drugs on Pioglitazone Systemic Exposure
* Daily for 7 days unless otherwise noted Mean ratio (with/without coadministered drug and no change = 1-fold) % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively The half-life of pioglitazone increased from 8.3 hours to 22.7 hours in the presence of gemfibrozil [see Dosage and Administration (2.3) and Drug Interactions (7.1)]§ Indicates duration of concomitant administration with highest twice-daily dose of topiramate from Day 14 onwards over the 22 days of study Additional decrease in active metabolites; 60% for M-III and 16% for M-IV
Coadministered Drug and Dosage Regimen Pioglitazone
Dose Regimen (mg)* Change in AUC Change in Cmax
Gemfibrozil 600 mg twice daily for 2 days (N = 12) 15 mg single dose ↑3.2-fold ↑6%
Ketoconazole 200 mgtwice daily for 7 days(N = 28) 45 mg ↑34% ↑14%
Rifampin 600 mgdaily for 5 days (N = 10) 30 mg single dose ↓54% ↓5%
Fexofenadine 60 mgtwice daily for 7 days (N = 23) 45 mg ↑1% 0%
Ranitidine 150 mgtwice daily for 4 days(N = 23) 45 mg ↓13% ↓16%
Nifedipine ER 30 mgdaily for 7 days(N = 23) 45 mg ↑5% ↑4%
Atorvastatin Ca 80 mgdaily for 7 days(N = 24) 45 mg ↓24% ↓31%
Theophylline 400 mgtwice daily for 7 days(N = 22) 45 mg ↓4% ↓2%
Topiramate 96 mg twice daily for 7 days§ (N = 26) 30 mg§ ↓15% 0%

Metformin hydrochloride

Table 19. Effect of Coadministered Drug on Plasma Metformin Systemic Exposure
* All metformin and coadministered drugs were given as single doses AUC = AUC0–∞ Ratio of arithmetic means§ Metformin hydrochloride extended-release tablets, 500 mg At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h
Coadministered Drug Dose of Coadministered Drug* Dose of Metformin* Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1
AUC Cmax
No dosing adjustments required for the following:
Glyburide 5 mg 500 mg§ 0.98 0.99
Furosemide 40 mg 850 mg 1.09 1.22
Nifedipine 10 mg 850 mg 1.16 1.21
Propranolol 40 mg 850 mg 0.9 0.94
Ibuprofen 400 mg 850 mg 1.05 1.07
Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see Warnings and Precautions (5) and Drug Interactions (7)].
Cimetidine 400 mg 850 mg 1.4 1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) and Drug Interactions (7)].
Topiramate 100 mg 500 mg 1.25 1.17
Table 20. Effect of Metformin on Coadministered Drug Systemic Exposure
* All metformin and coadministered drugs were given as single doses AUC = AUC0–∞ Ratio of arithmetic means, p-value of difference <0.05§ AUC0-24 hr reported Ratio of arithmetic means
Coadministered Drug Dose of Coadministered Drug* Dose of Metformin* Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1
AUC Cmax
No dosing adjustments required for the following:
Glyburide 5 mg 500 mg§ 0.78 0.63
Furosemide 40 mg 850 mg 0.87 0.69
Nifedipine 10 mg 850 mg 1.1§ 1.08
Propranolol 40 mg 850 mg 1.01§ 0.94
Ibuprofen 400 mg 850 mg 0.97 1.01
Cimetidine 400 mg 850 mg 0.95§ 1.01 provides trustworthy package insert and label information about marketed prescription drugs as submitted by manufacturers to the U.S. Food and Drug Administration. Package information is not reviewed or updated separately by Every individual prescription drug label and package insert entry contains a unique identifier which can be used to secure further details directly from the U.S. National Institutes of Health and/or the FDA.

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