# Presentation: 120323

## Topical Immunosuppressants (Calcineurin Inhibitors) - 

**Topical Immunosuppressants (Calcineurin Inhibitors) - **
**Animal Toxicology**

- Pediatric Advisory Committee Meeting
- February 15, 2005

- Barbara Hill, Ph.D.
- Division of Dermatologic and Dental Drug Products

## Objective

**Summarize the animal toxicology data available for two topical immunosuppressants (Calcineurin Inhibitors) that have been approved for the topical treatment of atopic dermatitis**
**Protopic (tacrolimus) ointment (12-8-00) and Elidel (pimecrolimus) cream (12-13-01)**

## Outline

**Structures**
**General Toxicology**
**Genetic Toxicology Studies**
**Carcinogenicity Studies**
**9 Month Oral Monkey Toxicology Study**
**Summary**

## Structures

_**Tacrolimus**_

_**Pimecrolimus**_

## 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**

## Genetic Toxicology

**An appropriate battery of in vitro and in vivo genotoxicity tests were conducted for tacrolimus and pimecrolimus**
**Tacrolimus and pimecrolimus were non-genotoxic**

## Carcinogenicity Studies

_**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)**

## Oral Carcinogenicity Studies - Lymphoma Signal

- a – mg/kg/day
- b – Multiple of human exposure based on maximum human AUC
- c – Inadequate systemic exposure after oral administration
- d – No Observed Effect Level

| Drug | Species | Dosea | Factorb | Result |
| --- | --- | --- | --- | --- |
| Protopic | Rat | 3 | 9X | Negativec |
| Protopic | Mouse | 5 | 3X | Negativec |
| Elidel | Mouse | 48 | 258-340X | Lymphoma |
| Elidel | Mouse | 15 | 60-133X | NOELd |

## Dermal Carcinogenicity Studies - Lymphoma Signal

| Drug | Species | Dosea | Factorb | Result |
| --- | --- | --- | --- | --- |
| Protopicc | Mouse | 3.5 | 26X | Lymphoma |
| Protopicc | Mouse | 1.1 | 10X | NOEL |
| Elidelc | Rat | 10d | 3.3X | Negative |
| Elidele | Mouse | 25 | 47X | Lymphoma |
| Elidele | Mouse | 10 | 17X | NOEL |
| Elidele | Mouse | 100 | 179-217X | Lymphomaf  |

- a – mg/kg/day
- b – Multiple of human exposure based on maximum human AUC
- c – Final market formulation; d – Highest possible dose
- e – Dissolved in ethanol (13 week studies); f – After 8 weeks

## Carcinogenicity Studies - Other Tumor Signal

| Drug | Route | Species | Dosea | Factorb | Result |
| --- | --- | --- | --- | --- | --- |
| Elidel | Oral | Rat (M&F) | 10 | 40X | BTc |
| Elidel | Oral | Rat (M) | 5 | 32X | BTc |
| Elidel | Oral | Rat (F) | 5 | 21X | NOEL |
| Elidel | Oral | Rat (M) | 1 | 1.1X | NOEL |
| Elideld | Dermal | Rat | 2e | 1.5X | FCATf |

- a – mg/kg/day
- b – Multiple of human exposure based on maximum human AUC
- c – Benign Thymoma; d – Final marketed formulation
- e – Lowest dose tested; f – Follicular cell adenoma of the Thyroid

## Lymphoma Mechanism

**Results of the rodent carcinogenicity studies indicate that systemic immunosuppression leads to lymphoma formation **
**It is not clear if the mechanism of lymphoma formation is the same for rodents and humans**

## Oral monkey toxicology study

**Oral doses of 0, 15, 45 and 120 mg/kg/day pimecrolimus administered for 39 weeks**
**High dose discontinued after 19 weeks due to mortality**
**Immunosuppressive related lymphoproliferative disorder (IRLD) noted in all dose groups**
** ****IRLD frequently progresses to lymphoma**

## Oral monkey toxicology studyIRLD signal

| Dose
(mg/kg/day) | Incidence | Signal appearance (weeks) |
| --- | --- | --- |
| 0 | 0/8 | N/A |
| 15 | 1/8 | 39 |
| 45 | 5/8 | 7a – 39 |
| 120 | 7/9 | 14 – 18 |

- a – one animal

## Oral monkey toxicology study

**IRLD was associated with lymphocryptovirus (Epstein Barr related virus)**
**IRLD exhibited a dose dependent expression**
**Opportunistic infections were noted in some animals in all dose groups**
**Three of the high dose monkeys with IRLD had concurrent leukemia**

## Oral monkey toxicology study

**A NOEL for IRLD was not established in this study**
**Low dose is 31X MRHD based on AUC**
**Mechanism of lymphoma formation appears to be the same for monkeys and humans**
**It is unknown if the mechanism of leukemia formation is the same for monkeys and humans**

## Oral monkey toxicology study

**Results from this study confirm that adequate systemic exposure to pimecrolimus could elicit lymphoma formation via a similar mechanism that has been established for tacrolimus in humans**

## Summary

**Protopic (tacrolimus) ointment and Elidel (pimecrolimus) cream are topical immunosuppressants**
**Neither tacrolimus or pimecrolimus exhibited a genotoxic signal**
**Tumorigenicity exhibited by tacrolimus and pimecrolimus appears to be mediated by a non-genotoxic mechanism (i.e., immunosuppression)**

## Summary

**A lymphoma signal was evident in a dermal 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**

## 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**

## Summary

**IRLD was noted in a 9 month oral monkey toxicology study conducted with pimecrolimus**** **
**Biologic plausibility of lymphoma formation in local lymph nodes can not be ruled out at this time**