# Presentation: 509366

## Toxicology Studies of TazaroteneJiaqin Yao, Ph.D., ToxicologistDivision of Dermatologic and Dental Drug ProductsFDA/CDER/OND/ODE V

## Tazarotene Toxicity Studies

**Oral administration of tazarotene in rats (3 to 6 months), dogs (4 to 9 months), and monkeys (1month to 1 year) produced effects that were characteristic of retinoid toxicity**
**Maximum systemic exposure (AUC) to tazarotenic acid in these studies was generally similar or greater than (dogs), or less than (rats and monkeys) systemic exposure in humans at the recommended daily oral dose (4.5 mg).**
**Primary target organs/systems included bone, liver (including serum lipids), kidney, heart, thymus, testis, and skin.**
**Tazarotene was not a genotoxic substance, neither was it a carcinogen in rats and mice.**

## Toxicity in Fertility and Early Embryonic Development

| Species | Gender | Dose
(mg/kg/day) | Route | AUCanimal/AUCh-oral | Results |
| --- | --- | --- | --- | --- | --- |
| Rats | Male | 1 | Oral | 0.3 | Mating  - no effect,
Fertility - no effect |
|  |  | 3 | Oral | 0.7 | Sperm count and density |
| Rats | Female | 2 | Oral | 0.6 | Mating  - no effect,
Fertility - no effect,
Estrus stages,
Developmental toxicity |

## Toxicity in Embryonic Development

| Species | Gender | Dose
(mg/kg/day) | Route | AUCanimal/AUCh-oral | Results |
| --- | --- | --- | --- | --- | --- |
| Rats | Female | 0.25 | Oral | 0.2 | Developmental delays,
Teratogenic effects,
Post-implantation loss |
| Rabbits | Female | 0.2 | Oral | 4.7 | Teratogenic effects,
Post-implantation loss |
| Rats | Female | 0.25 | Topical | 0.2 | Fetal body weight
Skeletal ossification |
| Rabbits | Female | 0.25 | Topical | 2.3 | Malformations |

## Toxicity in Prenatal and Postnatal Development

| Species | Gender | Dose
(mg/kg/day) | Route | AUCanimal/AUCh-oral | Results |
| --- | --- | --- | --- | --- | --- |
| Rats | Female | 1 | Oral | 1.1 | Developmental and behavior delays |
| Rats | Female | 1 | Oral | 0.4 | Stillbirths,
F1 survival and body weights, 
Malformations, Developmental delays, Reproductive capabilities of F1 females
NOAEL = 0.1 mg/kg/day |

## Male Reproductive Toxicity

| Species | Gender | Dose
(mg/kg/day) | Route | AUCanimal/AUCh-oral | Results |
| --- | --- | --- | --- | --- | --- |
| Rats | Male | 1 | Oral | 0.3 | Mating  - no effect,
Fertility - no effect |
|  |  | 3 | Oral | 0.7 | Sperm count and density |
| Dogs | Male | 1 | Oral | 1.9 | Testicular changes |
|  |  | 3 | Oral | 4.1 | Testicular changes,
Testis weight |

## Maximum Recommended Human Dose (mg/kg/day)

| Tazarotene* | Acitretin | Isotretinoin |
| --- | --- | --- |
| 0.075 | 0.83 | 2.0 |

**Maximum Recommended Human Dose (mg/kg/day)**

*** proposed**

## Lowest Teratogenic Dose (mg/kg/day)

| Species | Tazarotene | Acitretin a (Soriatane) | Etretinate b,c | Tretinoin b | Isotretinoin b (Accutane) |
| --- | --- | --- | --- | --- | --- |
| Human |  |  | 0.2 | N.D.  d | 0.4 |
| Primates |  |  | 5 | 7.5 | 5 |
| Hamsters |  |  | 2.8 | 1.25 | 25 |
| Rabbits | 0.2 | 0.6 | 2 | 2 – 10 | 10 |
| Rats | 0.25 – 1 | 15 | 2 – 8 | 0.4 – 2 | 150 |
| Mice |  | 3 | 4 | 4 | 100 |

**a****  Pharmac. Ther. 40:29-43, 1989**
**b****  Toxicology 57:117-161, 1989**
**c****  J. Am. Acad. Dermatol. 6:652-659, 1982**
**d****  Not detectable**

## Conclusions

**Human may be the most sensitive species for teratogenicity of retinoids.**
**Tazarotene is a more potent teratogen than other retinoids in rats and rabbits on a mg/kg/day basis.**
**Tazarotene is a probable human teratogen. **