1Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Topical Immunosuppressants Topical Immunosuppressants (Calcineurin Inhibitors) - (Calcineurin Inhibitors) -

Animal ToxicologyAnimal Toxicology

October 30, 2003

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

2Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Overall ObjectiveOverall 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)

3Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

OutlineOutline

• StructuresStructures• General ToxicologyGeneral Toxicology• Genetic Toxicology StudiesGenetic Toxicology Studies• Photoco-carcinogenicity StudiesPhotoco-carcinogenicity Studies• Carcinogenicity StudiesCarcinogenicity Studies• Overall SummaryOverall Summary

4Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

StructuresStructures

Tacrolimus PimecrolimusHO

OH3C

H3C

CH3

OH CH2O

N

O CH3

CH3

OCH3OHO

OO

H3C OCH3

O

N

Cl

O

H3C

CH3

OH

CH3

CH3

OCH3

OH3C

OH3C O CH3

OO

O

O

OH

5Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

General ToxicologyGeneral 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

6Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Genetic ToxicologyGenetic Toxicology

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

7Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Carcinogenic MechanismsCarcinogenic 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

8Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Photoco-carcinogenicity StudyPhotoco-carcinogenicity Study

• Objective:Objective:– To determine in a hairless mouse To determine in a hairless mouse

model if dermal test article model if dermal test article application combined with application combined with simulated sunlight exposure can simulated sunlight exposure can reduce the time to formation of reduce the time to formation of skin papillomas compared to skin papillomas compared to simulated sunlight exposure alonesimulated sunlight exposure alone

9Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Photoco-carcinogenicity StudyPhotoco-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

10Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Photoco-carcinogenicity StudyPhotoco-carcinogenicity Study

Tacrolimus• Vehicle ointment Vehicle ointment

enhanced UV enhanced UV photo-photo-carcinogenesis carcinogenesis

• Tacrolimus Tacrolimus ointment had an ointment had an additional small additional small effecteffect

Pimecrolimus• Vehicle cream Vehicle cream

enhanced UV photo-enhanced UV photo-carcinogenesis carcinogenesis

• Pimecrolimus cream Pimecrolimus cream had no additional had no additional effecteffect

11Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Photoco-carcinogenicity StudyPhotoco-carcinogenicity Study

• Result of nonclinical finding:– a precaution was included in the label of a precaution was included in the label of

each drug product advising patients to each drug product advising patients to minimize or avoid exposure to natural minimize or avoid exposure to natural or artificial sunlight while using the or artificial sunlight while using the drug productdrug product

12Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Carcinogenicity StudiesCarcinogenicity 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)

13Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Carcinogenicity StudiesCarcinogenicity 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)

14Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Oral Carcinogenicity Studies - Oral Carcinogenicity Studies - Lymphoma SignalLymphoma Signal

Drug Route Species Dosea;MRHD

Result

Protopic Oral Rat 3; 9X Negativeb

Protopic Oral Mouse 5; 3X Negativeb

Elidel Oral Mouse 45; 258-340X

Lymphoma

Elidel Oral Mouse 15; 60-133X

NOEL

a – mg/kg/dayb – Inadequate systemic exposure afteroral administration

15Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Dermal Carcinogenicity Dermal Carcinogenicity Studies - Lymphoma SignalStudies - Lymphoma Signal

Drug Route Species Dosea;MRHD

Result

Protopicb Dermal Mouse 3.5; 26X LymphomaProtopicb Dermal Mouse 1.1; 10X NOELElidelb Dermal Rat 10c; 3.3X NegativeElideld Dermal Mouse 25; 47X LymphomaElideld Dermal Mouse 10; 17X NOELElideld Dermal Mouse 100; 179-217X Lymphoma

(8 weeks)a – mg/kg/day; b – Final marketed formulationc – Highest possible dosed – Dissolved in ethanol (13 week studies)

16Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Carcinogenicity Studies - Other Carcinogenicity Studies - Other Tumor SignalTumor Signal

Drug Route Species Dosea;MRHD

Result

Elidel Oral Rat (M&F) 10; 40X Benign ThymomaElidel Oral Rat (M) 5; 32X Benign ThymomaElidel Oral Rat (F) 5; 21X NOELElidel Oral Rat (M) 1; 1.1X NOELElidelb Dermal Rat 2c; 1.5X FCATd

a – mg/kg/dayb – Final marketed formulationc – Lowest dose testedd – Follicular cell adenoma of the thyroid

17Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Overall SummaryOverall 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

18Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Overall SummaryOverall 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

19Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Overall SummaryOverall Summary

• The estimates of human systemic exposure data are highly variable and are dependent on the maximum body surface area that is body surface area that is treated in an atopic dermatitis patienttreated 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 It is acknowledged that demonstrating this effect could be demonstrating this effect could be technically challenging)technically challenging)

20Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Overall SummaryOverall 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

21Pediatric Subcommittee of the AIDAC Pediatric Subcommittee of the AIDAC October 29-30, 2003October 29-30, 2003

Overall SummaryOverall 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