azone
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 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 5 to 7 L/hr.
Special Populations
Renal Impairment
Alogliptin
A single-dose, open-label study was conducted to eva luate the pharmacokinetics of alogliptin 50 mg in patients with chronic renal impairment compared with healthy subjects. In patients with mild renal impairment (creatinine clearance [CrCl] ≥60 to <90 mL/min), an approximate 1.2-fold increase in plasma AUC of alogliptin was observed. Because increases of this magnitude are not considered clinically relevant, dose adjustment for patients with mild renal impairment is not recommended.
In patients with moderate renal impairment (CrCl ≥30 to <60 mL/min), an approximate two-fold increase in plasma AUC of alogliptin was observed. To maintain similar systemic exposures of OSENI to those with normal renal function, the recommended dose of OSENI is 12.5 mg/15 mg, 12.5 mg/30 mg or 12.5 mg/45 mg once daily in patients with moderate renal impairment.
In patients with severe renal impairment (CrCl ≥15 to <30 mL/min) and ESRD (CrCl <15 mL/min or requiring dialysis), approximate three- and four-fold increases in plasma AUC of alogliptin were observed, respectively. Dialysis removed approximately 7% of the drug during a three-hour dialysis session. OSENI is not recommended for patients with severe renal impairment or ESRD. Coadministration of pioglitazone and alogliptin 6.25 mg once daily based on individual requirements may be considered in these patients.
Pioglitazone
The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 50 mL/min) to severe (creatinine clearance <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
Alogliptin
Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. The magnitude of these reductions is not considered to be clinically meaningful. Patients with severe hepatic impairment (Child-Pugh Grade C) have not been studied. Use caution when administering OSENI to patients with liver disease [see Use in Specific Populations (8.6) and Warnings and Precautions (5.4)].
Pioglitazone
Compared with healthy controls, subjects with impaired hepatic function (Child-Pugh Grade B and C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III and M-IV) mean peak concentrations 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 u
