Table 1.
Summary of 24-month oral carcinogenicity study with dapagliflozin in mice
| Dapagliflozin dose (mg/kg per day): | Males | Females | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 0a (n = 60) | 0b (n = 60) | 5 (n = 60) | 15 (n = 60) | 40 (n = 60) | 0a (n = 60) | 0b (n = 60) | 2 (n = 60) | 10 (n = 60) | 20 (n = 60) | |
| C max at day 182, μg/mL | NA | NA | 1.04 | 3.20 | 14.1 | NA | NA | 1.09 | 6.25 | 16.0 |
| AUC(0–T) at day 182c, μg h/mL | NA | NA | 2.00 | 6.41 | 33.5 | NA | NA | 5.09 | 24.0 | 48.6 |
| No. survivors at termination, n (%) | 26 (43) | 24 (40) | 26 (43) | 18 (30) | 20 (33) | 28 (47) | 21 (35) | 19 (32) | 22 (37) | 25 (42) |
| Major causes of deathd, % | ||||||||||
| Urogenital system–non-neoplastic lesionse | 9 | 11 | 15 | 19 | 30 | 0 | 0 | 0 | 0 | 0 |
| Lymphoreticular system–neoplasms | 3 | 8 | 12 | 2 | 8 | 25 | 31 | 12 | 32 | 9 |
| Kidney–chronic progressive nephropathy | 6 | 3 | 3 | 0 | 3 | 6 | 15 | 20 | 11 | 6 |
| Amyloidosis | 12 | 11 | 12 | 10 | 8 | 6 | 3 | 12 | 3 | 9 |
| Uterus/cervix neoplasms | – | – | – | – | – | 22 | 8 | 2 | 13 | 3 |
| Lung neoplasms | 12 | 8 | 0 | 5 | 8 | 6 | 5 | 2 | 3 | 6 |
| Liver neoplasms | 12 | 3 | 3 | 5 | 0 | 0 | 0 | 2 | 0 | 3 |
| Heart–non-neoplastic lesions | 0 | 11 | 15 | 2 | 5 | 0 | 3 | 2 | 0 | 0 |
| Other causes | 14 | 28 | 25 | 12 | 20 | 19 | 14 | 28 | 25 | 35 |
| Not determined | 32 | 17 | 15 | 45 | 18 | 16 | 21 | 20 | 13 | 29 |
AUC (0–T) area under the plasma concentration–time curve from administration to last observed concentration at t, C max maximum observed plasma concentration, NA not applicable
aVehicle-control group
bWater-control group
cFor AUC(0–T), T = 8 h (males) or 24 h (females) post dose
dPercentage of pretermination deaths attributed to a specific cause
eNon-neoplastic urogenital system lesions (compatible with male mouse urologic syndrome) comprised combinations of the following: (1) kidney lesions (pyelitis, pyelonephritis, dilated pelves); (2) urinary bladder lesions (distended, erosions/subacute ulcers/chronic inflammation; (3) prostate gland and seminal vesicles (subacute/chronic inflammation, purulent inflammation/fibrosis, abscesses). Prostate and seminal vesicle effects are included as part of mouse urologic syndrome because they are commonly affected in mouse urologic syndrome, which is a common background lesion in male mice that results in inflammatory changes in urogenital tissues (including male accessory sex glands such as prostate and seminal vesicles) and partial to full urogenital obstruction, often presenting as urinary bladder dilatation