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Clinical Pharmacology and Biopharmaceutics Presentation for Oral Tazarotene (NDA 21-701)

Clinical Pharmacology and Biopharmaceutics Presentation for Oral Tazarotene (NDA 21-701). Tapash K. Ghosh, Ph. D. Office of Clinical Pharmacology and Biopharmaceutics CDER, FDA. Clinical Pharmacology and Biopharmaceutics Presentation. Focus of my presentation:

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Clinical Pharmacology and Biopharmaceutics Presentation for Oral Tazarotene (NDA 21-701)

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  1. Clinical Pharmacology and Biopharmaceutics Presentation for Oral Tazarotene (NDA 21-701) Tapash K. Ghosh, Ph. D. Office of Clinical Pharmacology and Biopharmaceutics CDER, FDA

  2. Clinical Pharmacology and Biopharmaceutics Presentation Focus of my presentation: • Pharmacokinetics (PK) of Tazarotene (TAZ) and Tazarotenic acid (TA) in plasma • Potential for drug-drug interactions • TA in Semen

  3. Proposed Mechanisms of Action TAZ/TA have multiple effects on keratinocyte differentiation and proliferation, as well as on inflammatory processes which may contribute to the pathogenesis of psoriasis. Some of them include: • Blocking of induction of epidermal ornithine decarboxylase activity • Suppression of expression of MRP8, a marker of inflammation present in the epidermis of subjects with psoriasis • Inhibition of cornified envelope formation, whose build-up is an element of the psoriatic scale expression

  4. Metabolism Scheme AGN190168 AGN190299 AGN190832 AGN190843 AGN190844

  5. Absorption • TAZ is well absorbed as approximately 90% of the oral 14C-tazoretene dose was recovered in feces and in urine as primarily TA and its metabolites. • TA exposure increases fairly in a dose proportional manner following oral TAZ dose from 3 mg to 6.3 mg.

  6. Distribution • TA is highly bound to plasma proteins, with an unbound fraction of less than 1%. • Following iv dose, the apparent volume of distribution of TAZ and TA were 3.55 L/kg and 0.75 L/kg, respectively.

  7. Metabolism • In humans, TAZ is hydrolyzed quickly and extensively to TA, the primary active moiety in the systemic circulation. • In vitro human metabolism studies demonstrated that TA is metabolized to an inactive sulfoxide metabolite (AGN 190844) via CYP and/or FMO enzymes in the liver.

  8. Elimination • Fecal elimination is the predominant elimination pathway, with 46.9% of the administered oral dose eliminated in the feces as TA. • Approximately 19.2% of the dose was excreted in the urine as the inactive sulfoxide metabolite of TA.

  9. Elimination • Following intravenous administration, TAZ was measurable in the plasma and was eliminated from the body with a mean terminal half-life of 6.2 hours. • Following intravenous administration, plasma TA concentration declined bi-exponentially with a mean terminal half-life of 13.8 hours.

  10. Elimination (continued) • Following intravenous administration, the systemic clearance of TAZ was 2.23 L/hr/kg • Systemic exposure of the active metabolite TA was 21.4 times that of the parent compound.

  11. Mean TA Plasma Concentration-Time profiles on Study Days 7 and 13

  12. Comparison of systemic exposure of TA from various topical and oral formulations

  13. Comparison of systemic exposure of TA from various topical and oral formulations However, the data obtained from topical gel was during maximal usage condition which may not reflect the usual usage condition.

  14. Drug - Drug Interaction • There was no interaction between TA and Ortho-Novum 1/35 and between TA and Ortho- Tri-Cyclen when given as oral TAZ dose of 6 mg. • Potential of drug-drug interactions involving CYP P450s especially 2C8 and 2B6 may need to be further explored.

  15. TA in Semen • Following once-daily dosing of TAZ 4.5 mg capsules for two weeks in healthy male subjects, > 79% semen samples had TA concentrations above the LLOQ (0.1 ng/mL) • Median semen to plasma TA concentration ratio at each predefined time point from semen samples over the 72-hr period was approximately 1 (one) or less except at 6 and 9 hr where the ratio was >1.

  16. TA in Semen • The highest individual semen to plasma TA concentration ratio was 2.8 and occurred between 9 and 12 hours post dose. • The highest mean (± SD, N) TA concentration observed in semen was 44.4 (± 22.2, 16) ng/ml occurred at 3 hours post dose. • The highest individual TA concentration observed in semen was 83.1 ng/ml occurred at 3 hours post dose (vs. 161.0 ng/mL peak plasma level).

  17. TA in Semen • Under worst case scenario, assuming an ejaculate volume of 10 mL, the amount of drug transferred in semen would be 831 ng which is about 1/ 5,000th of a single 4.5 mg capsule dose. • The no-effect limit for teratogenicity for TAZ/TA is unknown in humans.

  18. TA in Semen • Fertilized egg may remain exposed to TA in the semen following repeated sexual encounters. • Risk to a fetus, if any, while a male patient is taking the drug or after it is discontinued can not be ruled out.

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