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Topical Immunosuppressants (Calcineurin Inhibitors) - Animal Toxicology

Topical Immunosuppressants (Calcineurin Inhibitors) - Animal Toxicology. Barbara Hill, Ph.D. Division of Dermatologic and Dental Drug Products. October 30, 2003. Overall Objective.

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Topical Immunosuppressants (Calcineurin Inhibitors) - Animal Toxicology

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  1. Topical Immunosuppressants (Calcineurin Inhibitors) - Animal Toxicology Barbara Hill, Ph.D. Division of Dermatologic and Dental Drug Products October 30, 2003

  2. Overall Objective • Compare the animal toxicology data available for two topical immunosuppressants (Calcineurin Inhibitors) that have recently been approved for the topical treatment of atopic dermatitis • Protopic (tacrolimus) ointment (12-8-00) and Elidel (pimecrolimus) cream (12-13-01)

  3. Outline • Structures • General Toxicology • Genetic Toxicology Studies • Photoco-carcinogenicity Studies • Carcinogenicity Studies • Overall Summary

  4. Tacrolimus Pimecrolimus Structures

  5. General Toxicology • Potential immune target organs of toxicity identified in chronic rodent and nonrodent toxicology studies include thymus, lymph nodes and spleen • Nonclinical toxicology study results indicate both compounds are classic immunosuppressive agents

  6. Tacrolimus Conducted an appropriate battery of in vitro and in vivo genotoxicity tests Non-genotoxic Pimecrolimus Conducted an appropriate battery of in vitro and in vivo genotoxicity tests Non-genotoxic Genetic Toxicology

  7. Carcinogenic Mechanisms • Not all carcinogens are direct acting genotoxic (DNA reactive) agents • Indirect-acting carcinogens • Do not interact directly with DNA • Carcinogenesis is based on another mechanism • e.g., hormones, immunosuppressants

  8. Photoco-carcinogenicity Study • Objective: • To determine in a hairless mouse model if dermal test article application combined with simulated sunlight exposure can reduce the time to formation of skin papillomas compared to simulated sunlight exposure alone

  9. Photoco-carcinogenicity Study • A positive effect in this assay is referred to as an enhancement of the UV skin photo-carcinogenic effect, which is defined as shortening the time to skin tumor formation

  10. Tacrolimus Vehicle ointment enhanced UV photo-carcinogenesis Tacrolimus ointment had an additional small effect Pimecrolimus Vehicle cream enhanced UV photo-carcinogenesis Pimecrolimus cream had no additional effect Photoco-carcinogenicity Study

  11. Photoco-carcinogenicity Study • Result of nonclinical finding: • a precaution was included in the label of each drug product advising patients to minimize or avoid exposure to natural or artificial sunlight while using the drug product

  12. Tacrolimus Oral rat Oral mouse Dermal mouse (marketed formulation) Pimecrolimus Oral rat Oral mouse Dermal rat (marketed formulation) Dermal mouse (ethanol - 13 week; special high dose studies) Carcinogenicity Studies

  13. Carcinogenicity Studies • A treatment related tumor is identified as a statistically significant increase in the incidence of the tumor in treated animals compared to vehicle control animals • Treatment related tumors are expressed in both labels as a multiple of human exposure based on AUC comparisons to the maximum recommended human dose (MRHD)

  14. Oral Carcinogenicity Studies - Lymphoma Signal

  15. Dermal Carcinogenicity Studies - Lymphoma Signal

  16. Carcinogenicity Studies - Other Tumor Signal

  17. Overall Summary • Protopic (tacrolimus) ointment and Elidel (pimecrolimus) cream are topical immunosuppressants • Neither tacrolimus or pimecrolimus exhibited a genotoxic signal • Both Protopic ointment and Elidel cream contain cautionary wording in the labels to avoid sunlight exposure

  18. Overall Summary • A lymphoma signal was evident in adermal mouse carcinogenicity study conducted with tacrolimus ointment • A lymphoma signal was evident in an oral mouse carcinogenicity study conducted with pimecrolimus • A lymphoma signal was evident in the 13 week dermal mouse study conducted with pimecrolimus dissolved in ethanol

  19. Overall Summary • The estimates of human systemic exposure data are highly variable and are dependent on the maximum body surface area that is treated in an atopic dermatitis patient • Biologic plausibility of lymphoma formation in local lymph nodes can not be ruled out at this time (It is acknowledged that demonstrating this effect could be technically challenging)

  20. Overall Summary • Other tumor signals included: • Benign thymoma noted in the oral rat carcinogenicity study conducted with pimecrolimus • Follicular cell adenoma of the thyroid noted in the dermal rat carcinogenicity study conducted with pimecrolimus cream

  21. Overall Summary • Based on the carcinogenic signals noted in nonclinical studies, registry studies were recommended as a phase 4 commitment for both Protopic (tacrolimus) ointment and Elidel (pimecrolimus) cream

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