1 / 10

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

andrew
Télécharger la présentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related