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Published byJosephine Barber Modified over 9 years ago
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CA-1 Preclinical Studies Philip Bentley, PhD Vice President Toxicology/Pathology Novartis Pharmaceuticals Corporation Philip Bentley, PhD Vice President Toxicology/Pathology Novartis Pharmaceuticals Corporation
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CA-2 Tegaserod Carcinogenicity Studies Rat study: No tumor increase Mouse study: One tumor type increased Rat study: No tumor increase Mouse study: One tumor type increased
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CA-3 Increased Incidence of Intestinal Tumors in Tegaserod Mouse Carcinogenicity Study Dose, mg/kg060200600 SexMFMFMFMF No. of intestines118120606059606060 examined AdenocarcinomaSmall intestine00000062 Mucosal hyperplasiaSmall intestine00000087 Dose, mg/kg060200600 SexMFMFMFMF No. of intestines118120606059606060 examined AdenocarcinomaSmall intestine00000062 Mucosal hyperplasiaSmall intestine00000087 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)
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CA-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 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
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CA-5 Body Weight Curves in the Tegaserod Mouse Carcinogenicity Study
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CA-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 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
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CA-7 Tegaserod Induces Reversible Hyperplasia in Mouse Intestinal Mucosa Incidence of Study week Dose, mg/kgBrdU LIhyperplasia After 13-week 026.30/10 treatment200 30.2*2/10 600 35.2*6/10 After 4-week026.90/10 recovery20024.70/10 60027.80/10 Incidence of Study week Dose, mg/kgBrdU LIhyperplasia After 13-week 026.30/10 treatment200 30.2*2/10 600 35.2*6/10 After 4-week026.90/10 recovery20024.70/10 60027.80/10
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CA-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 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
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CA-9 Threshold Sustained Hyperplasia Is Required for Tumor Formation Hyperplasia Tumor 200 mg/kg 600 mg/kg
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CA-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 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
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CA-11 Tegaserod Therapy Poses No 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 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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