ioglitazone Systemic Exposure
Coadministered Drug and Dosage Regimen Pioglitazone
Dose Regimen (mg)* Change in AUC† Change in Cmax†
* Daily for seven days unless otherwise noted † Mean ratio (with/without coadministered drug and no change=one-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 6.5 hours to 15.1 hours in the presence of gemfibrozil [see DOSAGE AND ADMINISTRATION (2.3) and DRUG INTERACTIONS (7)]
Gemfibrozil 600 mg
twice daily for 2 days
(N=12) 30 mg
single dose ↑3.4-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%CLOSE
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Alogliptin and Pioglitazone
No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with OSENI. The following data are based on findings in studies performed with alogliptin or pioglitazone individually.
Alogliptin
Rats were administered oral doses of 75, 400 and 800 mg/kg alogliptin for two years. No drug-related tumors were observed up to 75 mg/kg or approximately 32 times the maximum recommended clinical dose of 25 mg, based on area under the plasma concentration curve (AUC) exposure. At higher doses (approximately 308 times the maximum recommended clinical dose of 25 mg), a combination of thyroid C-cell adenomas and carcinomas increased in male but not female rats. No drug-related tumors were observed in mice after administration of 50, 150 or 300 mg/kg alogliptin for two years, or up to approximately 51 times the maximum recommended clinical dose of 25 mg, based on AUC exposure.
Alogliptin was not mutagenic or clastogenic, with and without metabolic activation, in the Ames test with S. typhimurium and E. coli or the cytogenetic assay in mouse lymphoma cells. Alogliptin was negative in the in vivo mouse micronucleus study.
In a fertility study in rats, alogliptin had no adverse effects on early embryonic development, mating or fertility at doses up to 500 mg/kg, or approximately 172 times the clinical dose based on plasma drug exposure (AUC).
Pioglitazone
A two year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the MRHD of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg and above (approximately equal to the MRHD based on mg/m2). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg (approximately 1
