Pioglitazone pharmacokinetics and molecular data

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753

Pharmacokinetics

Absorption

Distribution

Metabolism

Excretion and Elimination

Renal Insufficiency

Hepatic Insufficiency

Elderly

Pediatrics

Gender

Ethnicity

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Absorption

Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Return to top

Distribution

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. Metabolites M-III and M-IV also are extensively bound (> 98%) to serum albumin. Return to top

Metabolism

Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and to a lesser degree CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Return to top

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. Return to top

Renal Insufficiency

The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended. Return to top

Hepatic Insufficiency

Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal. Return to top

Elderly

In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Return to top

Pediatrics

Pharmacokinetic data in the pediatric population are not available. Return to top

Gender

The mean Cmax and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, Pioglitazone improved glycemic control in both males and females. In controlled clinical trials, hemoglobin A1c (HbA1c) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Return to top

Ethnicity

Pharmacokinetic data among various ethnic groups are not available. Return to top

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The content of this page is taken from the FDA package insert for this drug and should not be edited.