1. Electronic Document Room Biostat Reviewer Doses, Survival
FDA
Electronic Document Room
Biostat Reviewer
Doses, Survival
Tumor incidence
Carcinogenicity study
Study report – pdf (SEND?)
Tumor data – xpt (SEND?)
13 week toxicity study
Human PK study
Study report – pdf (SDTM?)
Sponsor
Pharm/Tox Reviewer
Tumor incidence with statistical significance
Doses, Survival
AUCs (animal and human)
Result – labeling statement
“The NOAEL for tumors in mice was 30 mg/kg or 15 times the exposure in humans at the maximum recommended human dose.”
Clin Pharm Reviewer
Human Drug Conc.

2. FDA Biostat-generated table
NOAEL
FDA Biostat-generated table
Organ
Tumor type
Sex
Quantity
Control
Low
10 mg/kg
Mid
30 mg/kg
High
100 mg/kg
Mammary gland
Adenocarcinoma F
p-value of pairwise and trend tests
<0.0001
.1407
.0632
Poly-3 adjusted incidence rate
51%
62%
66%
91%
Observed number of cases 28 34 35 60 .

3. TK parameters from tox study report
Male
Female
Analyte
Dose (mg/kg)
Cmax (ng/mL)
AUC (ng∙h/mL)
Parent 10
3782
21895
3656
24000 30
10729
54005
6759
61500
100
23265
295346
11350
183867
AUC at NOAEL
PK parameter from Clin Pharm Review
Human AUC at maximum recommended human dose = 4150 ng∙h/mL
Animal to human AUC ratio at NOAEL
= ng∙h/mL  4150 ng∙h/mL= ≈ 15