AUC†

Cmax

* All doses administered as single dose unless otherwise specified. The 200 mg dose is 2 times the maximum recommended daily dose of sitagliptin. † AUC is reported as AUC 0-∞ unless otherwise specified. ‡ Multiple dose. § AUC 0-24hr. ¶ AUC 0-last. # AUC 0-12hr.  

No dosing adjustments required for the following: 

Digoxin 0.25 mg‡ once daily for 10 days 100 mg‡ once daily for 10 days Digoxin 1.11§ 1.18 

Glyburide 1.25 mg 200 mg‡ once daily for 6 days Glyburide 1.09 1.01 

Simvastatin 20 mg 200 mg‡ once daily for 5 days Simvastatin 0.85¶ 0.80 

Simvastatin Acid 1.12¶ 1.06 

Rosiglitazone 4 mg 200 mg‡ once daily for 5 days Rosiglitazone 0.98 0.99 

Warfarin 30 mg single dose on day 5 200 mg‡ once daily for 11 days S(-) Warfarin 0.95 0.89 

R(+) Warfarin 0.99 0.89 

Ethinyl estradiol and norethindrone 21 days once daily of 35 µg ethinyl estradiol with norethindrone 0.5 mg × 7 days, 0.75 mg × 7 days, 1.0 mg × 7 days 200 mg‡ once daily for 21 days Ethinyl estradiol 0.99 0.97 

Norethindrone 1.03 0.98 

Metformin 1,000 mg‡ twice daily for 14 days 50 mg‡ twice daily for 7 days Metformin 1.02# 0.97 

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis 

Ertugliflozin 

Carcinogenicity was eva luated in CD-1 mice and Sprague-Dawley rats. In the mouse study, ertugliflozin was administered by oral gavage at doses of 5, 15, and 40 mg/kg/day for up to 97 weeks in males and 102 weeks in females. There were no ertugliflozin-related neoplastic findings at doses up to 40 mg/kg/day (approximately 50 times human exposure at the maximum recommended human dose [MHRD] of 15 mg/day based on AUC). In the rat study, ertugliflozin was administered by oral gavage at doses of 1.5, 5, and 15 mg/kg/day for up to 92 weeks in females and 104 weeks in males. Ertugliflozin-related neoplastic findings included an increased incidence of adrenal medullary pheochromocytoma (PCC) in male rats at 15 mg/kg/day. Although the molecular mechanism remains unknown, this finding may be related to carbohydrate malabsorption leading to altered calcium homeostasis, which has been associated with PCC development in rats and has unclear relevance to human risk. The no-observed-effect level (NOEL) for neoplasia was 5 mg/kg/day (approximately 16 times human exposure at the MRHD of 15 mg/day, based on AUC).

Sitagliptin 

A two year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD.

A two year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD.

Mutagenesis