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

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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

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Pimecrolimus

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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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Systemic Pimecrolimus Exposure in Adults, Children and Infants on Day 4 following Topical bid Application of 1%

Cream

0

1

2

3

4

5

0 2 4 6 8 10 12 14

Sampling Time (hrs)

Co

nce

ntr

atio

n (n

g/m

l)

Adults (Study 204; n=12)Children (Study202; n=7)Infants (Study 301; n=7)Series2Series3Series4Series6Series7Series8Series9Series10Series12Series13Series14Series15Series16Series17

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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.

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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.

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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.

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Tacrolimus

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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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Tacrolimus Exposure in Adults and Children (6 - 12 yrs) Following Application of 0.1% Ointment

0

2

4

6

8

10

0 5 10 15

Days

Max

Ob

serv

ed C

(n

g/m

l)

Adults (n-32)Peds (n=20)Series3Series4Series5

12

0.03% Tacrolimus Ointment in Children (n= 14; 2 - 5yrs)

0

4

8

12

16

0 5 10 15

Days

Max

Ob

serv

ed C

(n

g/m

l)

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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

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Assessment of Bioavailability of Tacrolimus

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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.

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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.