1. Systemic Exposure of Topical Tacrolimus Veneeta Tandon, Ph.D. Pharmacokinetics Reviewer Division of Pharmaceutical Evaluation III Office of Clinical Pharmacology and Biopharmaceutics

2. Adult PK Studies In NDA In healthy volunteers (N=12) –single/multiple topical doses of 0.03, 0.1 and 0.3% tacrolimus ointment In patients (N=49, 0.1%; N=35, 0.3%) –single/multiple doses of 0.1 (N=17) & 0.3% ointment (N=4) –single/multiple doses of 0.1% ointment (N=32) –single/multiple doses of 0.3% ointment (N=31)

3. Adult Studies (0.1% Protopic™ ) Duration of the studies –b.i.d dosing for 13 days PK sampling on Day 1, 4 and 14 –b.i.d dosing for 7 days PK sampling on Day 1 and 7 Range of total BSA treated: 11-60% Number of patients with > 50% BSA treated= 8

4. Systemic Exposure of 0.1% Protopic™ From PK Studies In Adults Note: With more than 50% of the total BSA treated, all blood samples had detectable levels of tacrolimus NC=not calculable

5. Clinical Trials With Concentrations  5ng/mL From Random Sampling In Adults

6. Key Findings From a Study With 0.3% Tacrolimus Ointment In Adults Face and neck lesions in adults (N=7) are more permeable to the lesions on the trunk and limbs (N=6), leading to 4-7 times higher exposure of tacrolimus. A tendency for lower concentrations of tacrolimus on Day 8 (exception: face and neck regions of treatment).

7. Pediatric PK Studies in NDA In Pediatric Patients (N=20) –single/multiple doses of 0.1% ointment (N=20, ages 6-12)  No PK study conducted in the age range 2-5 years using 0.1% ointment –single/multiple doses of 0.3% ointment (N=8, ages 5-11)

8. Pediatric Studies (0.1% Protopic™ ) Duration of the study –b.i.d dosing for 13 days Age Range (6-12 years) Range of total BSA treated: 17-83% Number of patients with > 50% BSA treated= 8

9. Systemic Exposure of 0.1% Protopic™ From PK Studies In Pediatrics NC=not calculable

10. Key Findings From a Study with 0.3% Tacrolimus Ointment In Pediatrics The younger children (age 5-6 yrs, N=4) tended to have higher systemic exposure of tacrolimus compared to the older children (age 7-11 yrs, N=4) The older children (age 7-11 yrs) tended to have higher systemic exposure on Day 8 as compared to Day 1.

11. Highest Observed Concentrations in Clinical Trials From Random Sampling (Age 2-6yrs) Note: These concentrations do not necessarily represent the true Cmax

12. Systemic Absorption of Topical Tacrolimus Compared to Oral Tacrolimus a AUC(0-  )

13. Conclusions Adults Systemic absorption of tacrolimus in adults, after topical application of 0.1%, is lower than the exposure generated from oral dosing for transplant rejection. Pediatrics An insufficient number of subjects were enrolled in the PK studies to assess the systemic absorption of tacrolimus in pediatric patients below the age of 5 under maximal use conditions. Further work in this target population should be considered.