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Preclinical Studies. Philip Bentley, PhD Vice President Toxicology/Pathology Novartis Pharmaceuticals Corporation. Tegaserod Carcinogenicity Studies. Rat study: No tumor increase Mouse study: One tumor type increased.

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preclinical studies

Preclinical Studies

Philip Bentley, PhD

Vice President Toxicology/Pathology

Novartis Pharmaceuticals Corporation

tegaserod carcinogenicity studies

Tegaserod Carcinogenicity Studies

Rat study: No tumor increase

Mouse study: One tumor type increased

increased incidence of intestinal tumors in tegaserod mouse carcinogenicity study
Increased Incidence of Intestinal Tumors in Tegaserod Mouse Carcinogenicity Study

Dose, mg/kg 0 60 200 600 Sex M F M F M F M FNo. of intestines 118 120 60 60 59 60 60 60 examined

Adenocarcinoma Small intestine 0 0 0 0 0 0 6 2

Mucosal hyperplasia Small intestine 0 0 0 0 0 0 8 7

200 mg/kg = 34 times human exposure (AUC); 80 fold human dose (BSA)

600 mg/kg = 70 times human exposure (AUC); 240 fold human dose (BSA)

mouse small intestinal tumors
Mouse Small Intestinal Tumors
  • Increased incidence at high dose only, which caused severe inhibition of body weight gain and exceeded the Maximal Tolerated Dose (MTD)
  • Associated with sustained hyperplasia of small intestinal mucosa
tegaserod has no mutagenic potential
Tegaserod Has No Mutagenic Potential
  • In vitro assays
    • Ames test, Salmonella typhimurium
    • Chromosomal aberration, V-79 cells
    • HGPRT gene mutation, V-79 cells
    • DNA repair (UDS), rat hepatocytes
  • In vivo assay
    • Bone marrow micronucleus, CD-1 mouse
tegaserod induces reversible hyperplasia in mouse intestinal mucosa
Tegaserod Induces Reversible Hyperplasia in Mouse Intestinal Mucosa

Incidence ofStudy week Dose, mg/kg BrdU LI hyperplasia

After 13-week 0 26.3 0/10

treatment 200 30.2* 2/10

600 35.2* 6/10

After 4-week 0 26.9 0/10

recovery 200 24.7 0/10

600 27.8 0/10

tumors result from epigenetic effects
Tumors Result From Epigenetic Effects
  • Short-term treatment of mice resulted in reversible hyperplasia of small intestinal mucosa
  • Long-term treatment at very high doses resulted in sustained mucosal hyperplasia as observed in the mouse carcinogenicity study
sustained hyperplasia is required for tumor formation
Sustained Hyperplasia Is Required for Tumor Formation

600 mg/kg

Threshold

200 mg/kg

Tumor

Hyperplasia

the tumor incidence was only increased at a very high tegaserod dose
The Tumor Incidence Was Only Increased at a Very High Tegaserod Dose
  • The dose of 600 mg/kg was above the MTD:
    • 1,800-fold human dose (240 fold BSA)
    • 70-fold expected human exposure (AUC)
    • 570-fold estimated local intestinal concentration
  • The no-effect level of 200 mg/kg was at the MTD:
    • 600-fold human dose (80 fold BSA)
    • 34-fold expected human exposure (AUC)
    • 190-fold estimated local intestinal concentration

BSA = Body surface area

tegaserod therapy poses no carcinogenic risk
Tegaserod Therapy PosesNo Carcinogenic Risk
  • Tegaserod is not mutagenic
  • Tumor incidences only increased at single site
  • No intestinal mucosal hyperplasia in dogs or rats
  • Initial hyperplasia in mice reversible
  • No carcinogenic effects in rats
  • Tumors only at the high dose in the mouse
    • Very high safety margin