1. 112901 LKPershing Bioequivalence Assessment of three 0.025% tretinoin gel products: Dermatopharmacokinetic vs. Clinical Trial Methods Lynn K. Pershing, Ph.D. Department of Dermatology University of Utah Salt Lake City, UT 84132

2. 112901 LKPershing Common Goal Best Therapeutic Products Innovator Industry Generic Industry Physicians Consumer FDA Scientists Health Care Insurance CROs

3. 112901 LKPershing Hypothesis The dermatopharmacokinetic (DPK) method will assess the BIOEQUIVALENCE of three 0.025% tretinoin gel products similar to the Clinical Efficacy/Safety Trial method

4. 112901 LKPershing Bioequivalence How much different can two topical products be and still be bioequivalent?

5. 112901 LKPershing Bioequivalence Q1 Q2 similar Q1Q2 Qualitatively similarQuantitatively similar same same Vehicle components[Vehicle components]

6. 112901 LKPershing Bioavailability Q1 Q2 different Q1Q2 Qualitatively differentQuantitatively different different different [active] Vehicle componentsdifferent [Vehicle components]

7. 112901 LKPershing Tretinoin gel, 0.025% A Ortho Reference B Bertek Test 1 C Spears Test 2 Butylated hydroxy toluene Hydroxypropyl cellulose Hydroxypropyl cellulose Hydroxypropyl cellulose Alcohol 90% (w/w)Polyolprepolymer-2 Ethanol 83% (w/w) Denatured with tert-butyl alcohol and brucine sulfate Alcohol 90% (w/w)

8. 112901 LKPershing Bioequivalence Assessment Clinical Efficacy/Safety Acne Trial Clinical Parameter Ortho vs. Spear Q1 Q2 similar Ortho vs. Bertek Q1 Q2 different EfficacyBENot BE Ortho > Bertek SafetyBENot BE Bertek 2X > Ortho

9. 112901 LKPershing Topical Drug Delivery

10. 112901 LKPershing Adhesive disc

11. 112901 LKPershing SC Drug Disposition Influence Of Weight Removed On Drug Concentration Gradient

12. 112901 LKPershing Bioanalytical Assay Validation TretinoinIsotretinoin Recovery>89.7%>87.0% InterferencesNoneNone Linear regression0.99630.9961 Accuracy>87%>85% Precision< 8%<11% Assay parameters –Calibration stds4-100 ng/mL4-100 ng/mL –LOQ4 ng/mL4 ng/mL Stability –Pre-extraction -70 o C storage4 week4 week Benchtop2 hrs2 hrs –Post-extraction Autosampler112 hrs112 hrs Freeze thaw 1 cycle1 cycle

13. 112901 LKPershing Product Dosing: 0.025% Tretinoin Gel 250 mcL syringe

14. 112901 LKPershing DPK Experimental Design UPTAKEELIMINATION

15. 112901 LKPershing Product Application Randomization tretinoin gel, 0.025%

16. 112901 LKPershing BE Study Demographics Subject #GenderAge (yrs) Mean (SD) EthnicityHand Preference 29 20 Female Male 31.2 (10.7) 29.5 (8.3) 25 C, 3 A, 1 H 16 C, 3 A, 1 H 29 R, 0 L 16 R, 4 L 49TOTAL30.7 (9.4)41 C, 6 A, 2 H45 R, 4 L

17. 112901 LKPershing Surface Area Considerations Treated Skin Site vs. Adhesive Disc

18. 112901 LKPershing DPK Bioequivalence tretinoin gel, 0.025%

19. 112901 LKPershing DPK Bioequivalence Tretinoin

20. 112901 LKPershing DPK Bioequivalence tretinoin gel, 0.025%

21. 112901 LKPershing DPK Bioequivalence Isotretinoin

22. 112901 LKPershing DPK Bioequivalence tretinoin gel, 0.025%

23. 112901 LKPershing DPK Bioequivalence Total Retinoids

24. 112901 LKPershing Bioequivalence Assessment of Three 0.025% tretinoin gel products Method Ortho vs. Spears Q1 Q2 similar Ortho vs. Bertek Q1 Q2 different DPKBENot BE Ortho 2x > Bertek Clinical EfficacyBENot BE Ortho > Bertek Clinical SafetyBENot BE Bertek 2x > Ortho

25. 112901 LKPershing DPK Method for Bioequivalence Assessment Objective Sensitive Discriminating Precise Accurate Relevant –Scientifically –Clinically Comparable PK method used for oral solid dosage products

26. 112901 LKPershing CONCLUSIONS DPK Method for Bioequivalence Assessment 0.025% tretinoin gel DPK results predict Clinical Efficacy Results DPK provides mechanistic basis for Safety Results DPK is sensitive, reproducible and valid method for BE assessment