Sign Out
Oral hypoglycemic agent.
Pharmacology: Pharmacodynamics: Pioglitazone, a potent and highly selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is a thiazolidinedione oral antidiabetic agent that acts primarily by reducing insulin resistance. It improves glycemic control by increasing insulin sensitivity in target tissues, primarily skeletal muscle and adipose tissue, and by decreasing hepatic gluconeogenesis.
Activation of PPARγ nuclear receptors, which are found in key target tissues for insulin action (eg, adipose tissue, skeletal muscle, liver), modulates the transcription of insulin-responsive genes involved in the control of glucose and lipid metabolism.
Like other thiazolidinediones, pioglitazone minimizes the risk of hypoglycemia associated with the treatment of type 2 diabetes by decreasing insulin resistance without stimulating insulin release from pancreatic β-cells.
Pharmacokinetics: Pioglitazone is absorbed rapidly with peak plasma concentrations occurring within 2 hrs after oral administration (fasting state). Repeated dosing does not result in accumulation of pioglitazone or metabolites. Pioglitazone is >80% bioavailable. While food slightly delays pioglitazone's absorption, the extent of absorption is not altered.
Pioglitazone is >99% plasma protein-bound and its mean apparent volume of distribution after single-dose administration is about 0.63±0.41 L/kg bodyweight. Metabolites MIII and MIV are also extensively bound to serum albumin (>98%).
Pioglitazone is extensively metabolized by hydroxylation and oxidation through the cytochrome P-450 isoforms (mainly CYP2C8 and to a lesser degree CYP3A4, with additional contributions from other isoforms including the mainly extrahepatic CYP1A1); the metabolites are also partly converted to glucuronide or sulfate conjugates. M-II, M-III and M-IV are its pharmacologically active metabolites. Studies of pioglitazone in combination with P450 inhibitors and substrates have been performed and have shown that pioglitazone is not a strong CYP3A4 enzyme inducer.
Steady-state serum concentrations of both pioglitazone and total pioglitazone (pioglitazone plus active metabolites) are achieved within 7 days. At steady state, 2 of the pharmacologically active metabolites of pioglitazone, MIII and MIV, reach serum concentrations equal to or greater than pioglitazone. At steady state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30-50% of the peak total pioglitazone concentrations and 20-25% of the total area under the serum concentration-time-curve (AUC).
Peak plasma concentration (Cmax), AUC and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg/day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg/day.
Pioglitazone is primarily excreted through the bile as unchanged drug or as metabolites and eliminated in the feces. About 15-30% of an oral pioglitazone dose is recovered in the urine (as metabolites and its conjugates); its renal elimination is negligible. Pioglitazone’s plasma elimination t½ is up to 7 hrs while its active metabolites have a t½ of up to 24 hrs.
Special Populations: Renal Insufficiency: Compared with normal subjects, the serum elimination t½ of pioglitazone, M-III and M-IV remains unchanged in patients with moderate [creatinine clearance (CrCl) 30-60 mL/min] to severe (CrCl <30 mL/min) renal impairment.
Hepatic Insufficiency: Compared with normal subjects, patients with hepatic dysfunction (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak plasma concentrations and no change in the mean AUC values. Do not initiate the drug in patients who exhibit clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal.
Elderly: Peak serum concentrations of pioglitazone and total pioglitazone are not significantly different in healthy elderly subjects. However, the AUC values in these patients are slightly higher and the terminal t½ values slightly longer than for younger subjects. These changes are considered to be clinically irrelevant.
