A Comprehensive Approach to Topical Bioequivalence Thomas J. Franz

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1 SKIN FORUM Presentation, June 26, 2013 A Comprehensive Approach to Topical Bioequivalence Thomas J. Franz

2 (Partial) Hierarchy of Surrogate Tests IVRT Tape Stripping TEWL / Exfol. Skin Irritation Vasoconstriction Microdialysis IVPT (Blood) Veh SC Epi Dermis

3 Nizoral Lemmon Generic ##1 083 Lemmon Generic ##2 074 Lemmon Generic ##3 080 Ketoconazole In Vitro Percutaneous Absorption 19% PG; 4.2% IPM µg/cm 2 /hr Nizoral % PG; 3.3% IPM 10% PG; 10% IPM Time (hr)

4 µg/cm 2 /hr Ketoconazole In Vitro Percutaneous Absorption 18% PG; 8% IPM 16% PG; 8% IPM Nizoral 16% PG; 4.2% IPM Nizoral Lemmon's Generic # A Lemmon's Generic # B Lemmon's Generic # C Time (hr)

5 Rate of Release Assay: Diprolene (Betametasone dipropionate) First test of new generic Cum Penetraiton (ug) Diprolene Generic Time (hr 1/2 ) Lehman 07Sept04

6 0.6 Rate of Release Assay: Diprolene Evaluation of different petrolatum sources to determine cause for generic difference. Selected for new generic Rate of Release Original Generic 0.0 Diprolene Pet #1 Pet #2 Pet #3 Pet #4 Pet #5 Pet #6 Pet #7 Formulation Lehman 07Sept04

7 30 Rate of Release Assay: Cum Penetration (ug) Innovator Generic Time (hr 1/2 ) Lehman 07Sept04

8 (Partial) Hierarchy of Surrogate Tests IVRT Tape Stripping TEWL / Exfol. Skin Irritation Vasoconstriction Microdialysis IVPT (Blood) Veh SC Epi Dermis

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10 Topical BE: Tape Stripping (Mean ± SEM) Amount Recovered (µg) (*2) Hydrocortisone Tape Strip Study 2 Hr Exposure, No Occlusion Hytone 1% Cortizone 1% Method 6 subjects Vent. Forearm A = 2 cm x 5 cm Dose = 1.9 mg/cm 2 1 Transpore tape, 22 strips pooled (2, 5, 5, 5, 5) Extract in methanol Assay by HPLC Tape Strip Set (5 tapes/set)

11 Topical BE: Tape Stripping (Mean ± SEM) Hydrocortisone Tape Strip Study 8 Hr Exposure, No Occlusion Amount Recovered (µg) (*2) Hytone 1% Cortizone 1% Tape Strip Set (5 strips/set)

12 Topical BE: Tape Stripping (Mean ± SEM) Amount Recovered (µg) Tape Strips # Only Hytone 1% Cortizone 1% Hydrocortisone Tape Stripping Study 2 hr NOC 8 hr NOC 8 hr OC 16 hr OC Exposure Conditions

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14 IVRT: Hydrocortisone Cumulative Release ( grams/cm 2 ) Hours 1/2 Cortizone 10, Hytone 1%, Hytone 2.5%

15 Total Penetration (µg) Melanex 3% Nudit 2% Porcelana 2% Solaquin Forte 4% Solaquin Forte 4% In Vitro Cadaver Skin Assay Esoterica 2% Eldopaque Forte 4% Hydroquinone Products (HPLC) Eldoquin Forte 4% Nadinola 2% Eldoquin 2% 0 Formulation Mean ± SE Lehman 07Sept04

16 Hydroquinone Absorption 14 Flux ( g/cm 2 /hr) Melanex (3% HQ) Eldoquin Forte (4% HQ) Hours

17 Hydroquinone Absorption 45 Hydroquinone Blister Data Summary 5 subjects 31.56±11.18 Concentration (µg/ml) Mean ± se 5.55± ± ±0.36 EF 10 min Mx 10 min EF 4 hr Mx 4 hr Dosed after Blistering Dosed before Blistering Drug/Dosing

18 ANTIFUNGALS IVRT Tape Stripping Skin Irritation IVPT Veh SC Epi Dermis (1) sensitivity, (2) rate + extent of absorption, (3) relative systemic toxicity Franz TJ, Lehman PA, Raney SG: Use of excised human skin to assess the bioequivalence of topical products. Skin Pharmacol and Physiol 22: , 2009.

19 RETINOIDS Veh SC Epi Dermis IVRT TEWL Skin Irritation IVPT Lehman PA, Franz TJ: Assessing the bioequivalence of topical retinoid products by pharmacodynamics assay. Skin Pharmacol and Physiol 25: , 2012.

20 Peeling Score Chromameter % Retin-A Cream 15 TEWL Peeling Erythema 10 TEWL Study Day 0

21 Validation: TEWL Test Tretinoin Gels Two Primary Endpoints: (1) maximum transepidermal water loss achieved (2) days to full peel (DTFP)

22 Tretinoin Gel: TEWL/Exfoliation 10 Relative TEWL (g/m 2 /hr) % gel 0.010% gel Placebo gel Study Day

23 TEWL max (g/m 2 /hr) Validation: TEWL Test Tretinoin Gels Maximum TEWL Generic Innovator 10 8 Placebo Product Labeled Potency (% Tretinoin)

24 Validation: TEWL Test Tretinoin Gels Statistical Analysis Dose = 0.01% Classical CI on ratio (test/ref) TEWL: (93.9%, 114.7%) DTFP: (95.8%, 103.5%) Dose = 0.025% Classical CI on ratio (test/ref) TEWL: (97.8%, %) DTFP: (96.3%, 105.2%)

25 0.5 Validation: IVPT vs Clinical Trial 0.0 Tretinoin Gels 0.01% Gel Flux (ng/cm 2 /hr) Retin-A Spear 0.025% Gel Hours

26 Validation: IVPT vs Clinical Trial Tretinoin Gel 1.5 Retin-A Spear Flux (ng/cm 2 /hr) % Gel Hours

27 Validation: Skin Permeation Test Tretinoin 0.01% Gel Mean (Ln transformed data) Spear Retin-A Ratio 90% CI On Ratio AUC J max T max Franz TJ, Lehman PA, Raney SG: Use of excised human skin to assess the bioequivalence of topical products. Skin Pharmacol and Physiol 22: , 2009.

28 Validation: Skin Permeation Test Tretinoin 0.025% Gel Mean (Ln transformed data) Spear Retin-A Ratio 90% CI On Ratio AUC J max T max Franz TJ, Lehman PA, Raney SG: Use of excised human skin to assess the bioequivalence of topical products. Skin Pharmacol and Physiol 22: , 2009.

29 Summary Assessment of the BE of topical drug products can be accomplished through the use of appropriately selected in vitro and in vivo surrogate tests. All surrogate tests have limitations but they all don t have the same limitation. The results from one test complement the results of other tests. Selection of tests would depend upon the complexity of the formulation and whether the test product is Q1/Q2 equivalent. For most products IVRT, IVPT, and irritation testing would be essential.