Systemic Exposure of Topical Tacrolimus

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 (N12)
• single/multiple topical doses of 0.03, 0.1 and
  0.3 tacrolimus ointment
• In patients (N49, 0.1 N35, 0.3)
• single/multiple doses of 0.1 (N17) 0.3
  ointment (N4)
• single/multiple doses of 0.1 ointment (N32)
• single/multiple doses of 0.3 ointment (N31)

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 gt 50 BSA treated 8

4
Systemic Exposure of 0.1 Protopic From PK
Studies In Adults
NCnot calculable
Note With more than 50 of the total BSA
treated, all blood samples had detectable levels
of tacrolimus
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 (N7) are more
  permeable to the lesions on the trunk and limbs
  (N6), 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 (N20)
• single/multiple doses of 0.1 ointment (N20 ,
• 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 (N8,
• 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 gt 50 BSA treated 8

9
Systemic Exposure of 0.1 Protopic From PK
Studies In Pediatrics
NCnot calculable
10
Key Findings From a Study with 0.3 Tacrolimus
Ointment In Pediatrics

• The younger children (age 5-6 yrs, N4) tended to
  have higher systemic exposure of tacrolimus
  compared to the older children (age 7-11 yrs,
  N4)
• 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
aAUC(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.