1. 1 Systemic Human Exposure of Pimecrolimus and Tacrolimus Following Topical Application Tapash K. Ghosh, Ph.D. Office of Clinical Pharmacology and Biopharmaceutics February 15, 2005

2. 2 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

3. 3 Pimecrolimus

4. 4 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

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6. 6 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.

7. 7 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.

8. 8 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.

9. 9 Tacrolimus

10. 10 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.

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13. 13 Comparison of systemic absorption after Oral and Topical administration of Tacrolimus PopulationNRoute (Dose)Mean AUC (0-24) (ng.h/ml) Mean Cmax (ng/ml) Adult (AD)32Topical (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) 20Topical (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) 14Topical (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)1Topical (0.03% b.i.d for 14 days, 82% of total BSA) 206.7 (Day1)14.8 (Day1) Liver Transplant Pediatric Patients 9Oral (0.15-0.2 mg/kg/day) 337±16743.4±27.9 Kidney Transplant Adult Patients 26Oral (0.2 mg/kg/day) 203±4219.2±10.3

14. 14 Assessment of Bioavailability of Tacrolimus

15. 15 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.

16. 16 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.