12.3 Pharmacokinetics

Following once-daily administration of pioglitazone hydrochloride, 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.

C max , AUC, and trough serum concentrations (C min ) 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, T max of pioglitazone was within two hours. Food delays the T max to three to four hours but does not alter the extent of absorption (AUC).


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.


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)]. Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone hydrochloride showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

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 (t 1/2 ) 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.

Renal Impairment

The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance [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.

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 C max 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 hydrochloride and clinical trials have generally excluded patients with serum ALT >2.5 times the upper limit of the reference range. Use caution in patients with liver disease [see Warnings and Precautions (5.3)].

Geriatric Patients

In healthy elderly subjects, C max of pioglitazone was not significantly different, but AUC values were approximately 21% higher than those achieved in younger subjects. The mean t 1/2 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.

Pediatric Patients

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


The mean C max 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.


Pharmacokinetic data among various ethnic groups are not available.

Drug-Drug Interactions

*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

Table 15 . Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs
Coadministered Drug
Pioglitazone Dosage Regimen ( mg )* Name and Dose Regimens Change in AUC Change in C m a x
45 mg Warfarin
(N = 12) Daily loading then maintenance doses based PT and INR values R-Warfarin ↓3% R-Warfarin ↓2%
Quick’s Value = 35 ± 5% S-Warfarin ↓1% S-Warfarin ↑ 1%
45 mg Digoxin
(N = 12) 0.200 mg twice daily (loading dose) then 0.250 mg daily (maintenance dose, 7 days) ↑15% ↑17%
45 mg daily Oral Contraceptive
[Ethinyl Estradiol (EE) 0.035 mg EE ↓11% EE ↓13%
for 21 days (N = 35) plus Norethindrone (NE) 1 mg] for 21 days NE ↑3% NE ↓7%
45 mg Fexofenadine
(N = 23) 60 mg twice daily for 7 days ↑30% ↑37%
45 mg (N = 14) Glipizide
5 mg daily for 7 days ↓3% ↓8%
45 mg daily Metformin
for 8 days (N = 16) 1000 mg single dose on Day 8 ↓3% ↓5%
45 mg Midazolam
(N = 21) 7.5 mg single dose on Day 15 ↓26% ↓26%
45 mg Ranitidine
(N = 24) 150 mg twice daily for 7 days ↑1% ↓1%
45 mg daily for 4 days Nifedipine ER
(N = 24) 30 mg daily for 4 days ↓13% ↓17%
45 mg Atorvastatin Ca
(N = 25) 80 mg daily for 7 days ↓14% ↓23%
45 mg (N = 22) Theophylline
400 mg twice daily for 7 days ↑2% ↑5%

*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)]

Table 16 . Effect of Coadministered Drugs on Pioglitazone Systemic Exposure
Coadministered Drug and Dosage Regimen Dose Regimen ( mg )* Change in AUC Change in C m a x
Gemfibrozil 600 mg twice daily for 2 days (N = 12) 15 mg single dose ↑ 3.2-fold ↑ 6%
Ketoconazole 200 mg twice daily for 7 days (N = 28) 45 mg ↑34% ↑14%
Rifampin 600 mg daily for 5 days (N = 10) 30 mg single dose ↓ 54% ↓ 5%
Fexofenadine 60 mg twice daily for 7 days (N = 23) 45 mg ↑ 1% 0%
Ranitidine 150 mg twice daily for 4 days (N = 23) 45 mg ↓ 13% ↓ 16%
Nifedipine ER 30 mg daily for 7 days (N = 23) 45 mg ↑ 5% ↑ 4%
Atorvastatin Ca 80 mg daily for 7 days (N = 24) 45 mg ↓ 24% ↓ 31%
Theophylline 400 mg twice daily for 7 days (N = 22) 45 mg ↓ 4% ↓ 2%

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