# Presentation: 771802

## Systemic Human Exposure of Pimecrolimus and Tacrolimus Following Topical Application

- Tapash K. Ghosh, Ph.D.
- Office of Clinical Pharmacology and Biopharmaceutics
- February 15, 2005

## Outline

- Exposure from Pimecrolimus (Elidel) Cream 1% based on NDA 21-302
- Exposure in Adults
- Exposure in Children
- Exposure in Infants
- Exposure from Tacrolimus (Protopic) Ointment, 0.03 &, 0.1% based on NDA 50-777
- Exposure in Adults
- Exposure in Children
- Bioavailability

## Pimecrolimus

## Pimecrolimus Cream 1% bid in Adults, Children and Infants

| Study A (n=12) | Study B (n = 7)
 | Study C (n = 7)
 |
| --- | --- | --- |
| Adults
3 weeks
BSA: 15 – 59%
Max C (ng/ml): 1.4 ng/ml (Day 17)
Max AUC (0-12h) (ng.h/ml):  11.4 (Day 17)
AUC could be calculated from 2 patients on more than 2 sampling days | Age: 1 – 4 yrs
3 weeks
BSA: 20 – 70%
Max C (ng/ml): 1.8 ng/ml (Day 4)
Max AUC (0-12h) (ng.h/ml):  18.8 (Day 4)
AUC could be calculated from 3 patients on Day 4
 | Age: 4.9 – 11 mos
3 weeks
BSA: 25 – 58%
Max C (ng/ml): 2.6 ng/ml (Day 4)
AUC could not be calculated
 |

## Slide 5

## Summary (Adults)

- Pimecrolimus cream 1% to adult patients largely resulted in low (<0.5 ng/ml) blood concentrations of pimecrolimus.
- Maximum systemic pimecrolimus concentration was observed between day 2 and 4.
- There was no evidence for higher blood concentrations of pimecrolimus with increasing body surface area treated.

## Summary (Pediatrics)

- Pimecrolimus cream 1% to pediatric patients largely resulted in low (<0.5 ng/ml) blood concentrations of pimecrolimus.
- Maximum systemic pimecrolimus concentration was observed between day 2 and 4.
- In contrast to the adult population relatively higher proportion of subjects (30 – 75%) displayed blood concentration above 0.5 ng/ml.

## Overall Summary (Pimecrolimus)

- Pimecrolimus cream 1% indicated consistently low systemic exposure in adults, adolescents, children and infants with Atopic Dermatitis.
- Infants under 2 years of age were found to have relatively higher blood concentrations of Pimecrolimus compared to older children and adults.

## Tacrolimus

## Topical Tacrolimus Ointment bid in Adults and Children

| Study I (0.1%; n = 32) | Study II (0.1%; n = 20)
 | Study III (0.03%; n = 14)
 |
| --- | --- | --- |
| Adults 
BSA: 11 – 60%
3 weeks
Max C (ng/ml): 9.9 ng/ml (Day 4)
Max AUC (0-12h) (ng.h/ml):  31.0 (Day 4)
AUC could be calculated from almost all patients on each sampling day (1, 4 and 14) | Children (6-12 yrs) 
BSA: 17 – 83%
3 weeks
Max C (ng/ml): 1.5 ng/ml (Day 1)
Max AUC (0-12h) (ng.h/ml):  13.2 (Day 1)
AUC could be calculated from almost all patients on each sampling day (1, and 14) | Children (2-5 yrs) 
 BSA: 30 – 82%
3 weeks
Max C (ng/ml): 14.8 ng/ml (Day 1)
Max AUC (0-12h)* (ng.h/ml):  103.3 (Day 1)
AUC could be calculated from almost all patients on each sampling day (1, and 14)
*One patient showed persistently high level of tacrolimus throughout the 14 -day study period though affected % BSA improved significantly from 82% on Day 1 to 22% on Day 14. |

## Slide 11

## Slide 12

## Comparison of systemic absorption after Oral and Topical administration of Tacrolimus

| Population | N | Route (Dose) | Mean AUC (0-24) (ng.h/ml) | Mean Cmax (ng/ml) |
| --- | --- | --- | --- | --- |
| Adult (AD) | 32 | Topical (0.1% b.i.d for 13 days, 16-53% of total BSA)  | 20.4±18.4 (Day 4) | 0.96 ± 0.80 (Day 4) |
| Children (6-12yrs) (AD) | 20 | Topical 
(0.1% b.i.d for 13 days,
33-61% of total BSA)  | 10.6 ± 15.0 (Day 1)
 | 0.70 ± 0.98 (Day 1) |
| Children (2-5yrs) (AD)
 | 14 | Topical 
(0.03% b.i.d for 14 days,
37-82% of total BSA)  | 22.1±56.01 (Day 1) | 1.59 ± 4.01 (Day 1)
 |
| Child  (3 yr) | 1 | Topical 
(0.03% b.i.d for 14 days,
82% of total BSA) 
 | 206.7 (Day1) | 14.8 (Day1) |
| Liver Transplant Pediatric Patients  | 9 | Oral
(0.15-0.2 mg/kg/day)  | 337±167 | 43.4±27.9 |
| Kidney Transplant Adult Patients  | 26 | Oral
(0.2 mg/kg/day)  | 203±42 | 19.2±10.3 |

## Assessment of Bioavailability of Tacrolimus

## Overall Summary (Tacrolimus)

- On average, systemic exposure of tacrolimus from 0.1% tacrolimus ointment is low relative to the exposure generated from oral dosing. Occasionally, some subjects showed relatively high exposures.
- There are no significant differences in systemic exposure between adult and pediatric patients (2 -12 years of age).
- Systemic exposure tends to increase with increasing body surface area treated.

## Conclusions

- _Systemic Exposure_
- Both pimecrolimus and tacrolimus show systemic exposure following topical applications.
- More patients had detectable blood levels following topical applications of tacrolimus.
- Not much difference is noted in exposure between adult and children populations.
- _Regional Exposure_
- The amount of pimecrolimus and tacrolimus that enters the lymphatic system as well as its consequence following topical administration is unknown.