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Entereg ® ( Alvimopan) Capsules Adolor Corporation (Non-Clinical Findings)

Entereg ® ( Alvimopan) Capsules Adolor Corporation (Non-Clinical Findings) . Tamal K. Chakraborti, Ph.D. Pharmacologist United States Food and Drug Administration Center for Drug Evaluation and Research Division of Gastroenterology Products. Non-Clinical Studies. Pharmacology

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Entereg ® ( Alvimopan) Capsules Adolor Corporation (Non-Clinical Findings)

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  1. Entereg® (Alvimopan) CapsulesAdolor Corporation(Non-Clinical Findings) Tamal K. Chakraborti, Ph.D. Pharmacologist United States Food and Drug Administration Center for Drug Evaluation and Research Division of Gastroenterology Products

  2. Non-Clinical Studies • Pharmacology • Safety Pharmacology • ADME • Acute/Subacute/Subchronic/Chronic Toxicology • Genetic Toxicology • Carcinogenicity • Reproductive and Developmental Toxicology

  3. Cardiovascular Safety Pharmacology • hERG Assay: • No significant inhibition of hERG current • Dog Purkinje Fiber: • No significant effect • Rats (up to 200 mg/kg, Oral): • No significant effect • Dogs (up to 2.5 mg/kg, IV): • No significant effect

  4. Toxicology Studies • No significant toxicity in any organ • No effect on bones/bone marrow • No cardiac toxicity • No observed adverse effect level (NOAEL) • Rat: 200 mg/kg/day (6-month, PO) • Dog: 100 mg/kg/day (6-month, PO)

  5. Genotoxicity • Alvimopan • Ames test: Negative • Mouse lymphoma assay: Negative • Chromosomal aberration test: Negative • Rat micronucleus test: Negative • ADL 08-0011(Active Metabolite): • Ames test: Negative • Chromosomal Aberration test: Negative • Mouse micronucleus test: Negative

  6. Carcinogenicity Studies • Rat • 2-Year, Oral • Doses: 100, 200, 500 mg/kg/day • Mouse • 2-Year, Oral • Doses: 100, 1000, 4000 mg/kg/day

  7. Carcinogenicity (Neoplastic Findings) • MOUSE • Statistically significant positive trend and pairwise difference (vehicle versus 4000 mg/kg/day) in the incidences of fibroma, fibrosarcoma and sarcoma in the skin/subcutis of female mice • Statistically significant positive trend and pairwise difference (vehicle versus 4000 mg/kg/day) in the incidences of osteoma/osteosarcoma in bones of female mice • RAT: • Negative

  8. Mouse (Female) Tumor Incidences *: P < 0.025

  9. Carcinogenicity • 8-Times the human exposure at the recommended dose • Tumor incidences were statistically significant only in female mice • No statistically significant findings in male mice or in male or female rats • Relevance of this findings to human is unknown • Such tumor findings in female mice do not generally preclude approval

  10. SUMMARY • Safety Pharmacology: No notable effect • Toxicology: No significant target organ • Genetic Toxicology: Negative • Carcinogenicity: • Mice: Positive (female) • Rat: Negative • Reproductive Toxicology: • No adverse effect on fertility and reproductive performance in rats • Not teratogenic in rats and rabbits

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