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Pharmacology of Tacrolimus Ointment

Pharmacology of Tacrolimus Ointment William Fitzsimmons, Pharm.D. Vice President Drug Development Project Management Fujisawa Healthcare, Inc. Pharmacology of Tacrolimus Ointment. Topical macrolide (non-steroidal) immunomodulator

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Pharmacology of Tacrolimus Ointment

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  1. Pharmacology of TacrolimusOintmentWilliam Fitzsimmons, Pharm.D.Vice PresidentDrug Development Project Management Fujisawa Healthcare, Inc.

  2. Pharmacology ofTacrolimus Ointment • Topical macrolide (non-steroidal) immunomodulator • Inhibits calcineurin phosphatase activity in T-lymphocytes leading to decreased synthesis of cytokines associated with atopic dermatitis • Decreases inflammatory mediator release from skin mast cells and basophils

  3. Nonclinical Studies ofTacrolimus Ointment • 27 studies conducted • 3 chronic studies • 104-week topical carcinogenicity in B6C3F1 mice • 52-week photocarcinogenicity inhairless mice • 52-week topical toxicity in micropigs

  4. Topical Carcinogenicity Studyin Mice • 104 weeks (lifetime of animal) • No increase in skin tumors • Mice had 89 times higher systemic tacrolimus exposure than typical atopic dermatitis patients • Increased incidence of non-cutaneous lymphomas in 0.1% tacrolimus group

  5. Photocarcinogenicity Studyin Hairless Mice • 52 week study with controlled UVR exposure • All animals develop skin tumors • Median time to onset of tumor is the primary endpoint

  6. Photocarcinogencity in Hairless Mice(combined male & female) Tacrolimus (%) MTO (Weeks) Tumor Amplification Factor Untreated Control 42 1.0 Vehicle 34 1.3 0.03 35 1.3 0.1 34 1.3 0.3 31 1.5 1.0 31 1.5 MTO: Median Tumor Onset: mortality adjusted time at which one-half of the group has one or more tumors > 1 mm2. Tumor Amplification Factor: relative influence of a test article on the response of skin to UVR exposure.

  7. Topical Toxicity Studyin Micropigs • 52 weeks • Micropig (juvenile to adult) • Up to 3% tacrolimus ointment • Blood levels similar to humans • 40% Body Surface Area treated • No noteworthy topical or systemic findings

  8. Nonclinical StudiesConclusions • Tacrolimus is not a mutagen or carcinogen • In a 2 year mouse study, there was no increase in skin tumors • In mice, high skin permeability and high blood levels resulted in immunosuppression and lymphoma • In a mouse model, median time to onset of photo-induced skin tumors is reduced with vehicle and active treatment • No noteworthy topical or systemic toxicity in micropigs

  9. Early Patch Testing in HumansTacrolimus Ointment • No evidence for: • Contact hypersensitivity • Phototoxicity • Photosensitization • Reduction of collagen synthesis in the skin

  10. Pharmacokinetic Study -008in Atopic Dermatitis Patients • 0.3% tacrolimus ointment • Single application on days 1 and 8 • Twice daily application days 2 through 7 • Protocol-defined area of application • Pediatric: 50 or 100 cm2 • Adult: 100 to 5000 cm2 • Minimal systemic absorption (bioavailability < 0.5%) • No systemic accumulation

  11. Phase III US StudiesDistribution of TacrolimusBlood Concentration0.03% Tacrolimus Ointment (n=195) (n=25)

  12. Phase II/III US StudiesBlood Concentrations-Pediatric Patients(n=78)0.03% Tacrolimus Ointment 87% 12% 1% 0% 0%

  13. Phase III US StudiesDistribution of TacrolimusBlood Concentration0.1% Tacrolimus Ointment (n=193) (n=30)

  14. Mean Blood Levels (ng/mL)0.1% Tacrolimus Ointment US Europe Visit Week 1 Week 12 Month 6 Month 12 N 26 18 - - Pediatric Mean 0.16 0.10 - - N 176 119 - - Adult Mean 0.33 0.20 - - N 282 251 219 62 Adult Mean 0.47 0.31 0.34 0.28

  15. Population Pharmacokinetic Analysis • 462 patients in US clinical trials • Average % BSA affected at baseline = 43% • Estimation of “typical” exposure • Nonlinear Mixed Effect Modeling (NONMEM) Steady state concentration 0.25 ng/mL AUC0-24 hours 6 ng•hr/mL • Similar in pediatrics

  16. HypotheticalWorst Case Systemic Exposure in Atopic Dermatitis Patients • European adult pharmacokinetic study • Application of 0.1% tacrolimus ointment • AUC0-24 hours = 20 ng•hr/mL • Model assumptions(contrary to clinical evidence) • lesions don’t heal • % affected BSA doesn’t decrease • quantifiable blood concentration for prolonged periods

  17. Comparative AUC forTacrolimus Blood Levels Typical AD Patient Hypothetical Worst Case AD Patient Transplant Patient Transplant Patient with PTLD Mice with Lymphoma Cumulative AUC 122 days 732 1,410 55,144 79,208 65,392

  18. Relative Cumulative Systemic Exposure of TacrolimusBased on Blood Levels Relative to AD Patients: Transplant Recipients Transplant Recipients with PTLD Mice with Lymphoma “Typical” Case 75x 108x 89x Hypothetical “Worst” Case 39x 56x 46x

  19. Clinical PharmacologyConclusion • Minimal systemic absorption • Most patients do not have quantifiable levels • No systemic accumulation • Levels are transient • Pediatric patients have a lower frequency of detectable blood levels and lower average levels than adults • Large safety margin in comparison to immunosuppressed transplant patients or mice

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