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Preclinical Studies

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

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  1. Preclinical Studies Philip Bentley, PhD Vice President Toxicology/Pathology Novartis Pharmaceuticals Corporation

  2. Tegaserod Carcinogenicity Studies Rat study: No tumor increase Mouse study: One tumor type increased

  3. 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)

  4. 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

  5. Body Weight Curves in the Tegaserod Mouse Carcinogenicity Study

  6. 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

  7. 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

  8. 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

  9. Sustained Hyperplasia Is Required for Tumor Formation 600 mg/kg Threshold 200 mg/kg Tumor Hyperplasia

  10. 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

  11. 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

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