Amorolfine nail lacquer in onychomycosis

1. Amorolfine nail lacquer in onychomycosis

2. Amorolfine • Chemically stable Data on file; Galderma International

3. Amorolfine: mode of action Dual inhibition of sterol biosynthesis very potent fungistatic agent + fungicidal agent Kerkenaar A. Ed.RA Fromtling, 1987 Polak A et al., Handbook of Experimental Pharmacology, 1990

4. Antifungal Activity of Amorolfine In Vitro Polak A et al, Ed. RA Fromtling, 1987

5. Antifungal Activity of Amorolfine In VitroSummary Broad spectrum activity • Dermatophytes • Yeasts • Moulds Polak A et al, Ed. RA Fromtling, 1987 Polak A et al, Handbook of Exp Pharmacol, 1990 

6. Amorolfine: mode of action 24h-culture with 8ng/ml of Amorolfine 48h-culture with 80ng/ml of Amorolfine Control Dermatophytes Nishiyama Y. et al, Clin Exp Dermatol 1992

7. Amorolfine: mode of action Survival curve of yeasts - concentration of 3 microgrammes killed up to 100% of the cells in 7 days Polak A. et al., Handbook of Experimental Pharmacology 1990 Hay R., 8th EADV, 1999

8. Amorolfine: mode of action Control 24h-culture with 100μg/ml of Amorolfine 48h-culture with 100μg/ml of Amorolfine Yeasts Muller J. et al., Clin Exp Dermatol 1992

9. Amorolfine: Resistance • 400 strains of Candida sp. And Trichophyton sp. were used for sensitivity testing. • 20 strains of Candida albicans and 3 strains of Trichophyton were used to test the resistance frequency and selection of resistant mutants. None of the 400 strains tested for sensitivity showed primary resistance to amorolfine, and no fully resistant strains were detected. Polak A., Research Report B-102’098 1988

10. ONYCHOMYCOSISRationale for topical therapy Systemic drugs • Failure rate at least 20-25% • Systemic side effects • Drug interactions • Risk of resistance • High cost Topical • Compliance • Local care • Safe • Lower cost Epstein E., Arch Dermatol 1998

11. Amorolfine nail lacquer:Galenic characteristics

12. Amorolfine nail lacquer Formulation AMOROLFINE Solution Active - 5% Polymer (methacrylic acid copolymer) Plasticizer (triacetin) Solvent (ethanol) Marty J., Eur Ac Dermatol Venereol 1995

13. Amorolfine nail lacquer Selection of vehicle Vehicle: Compatible with active ingredient, optimises penetration Molecule characteristics: Hydrophilicity, partition coefficient Nail structure: Keratin, low % lipids, water gel membrane

14. Amorolfine nail lacquer Penetration - Vehicle Film (Polymer + Plasticizer) Solvent (ethanol) evaporation INCREASED PENETRATION Occlusion Hyperconcentration (amorolfine 25%) Marty J.P.; J. Eur. Acad. Dermatol. Venereol. 1995

15. Why is the degree of penetration so important?

16. OnychomycosisClinical Forms SUPERFICIAL ONYCHOMYCOSIS Courtesy Baran R., Hay R., Tosti A. & Haneke E., 1998

17. OnychomycosisClinical Forms DISTAL SUBUNGUAL ONYCHOMYCOSIS Ref: Baran, Hay, Tosti & Haneke, 1998 Courtesy Baran R., Hay R., Tosti A. & Haneke E., 1998

18. Amorolfine nail lacquer Penetration studies • Amorolfine penetrates efficiently into the nail plate • Amorolfine permeates through the horny tissue into the nail bed • Amorolfine accumulates to high enough concentrations for long enough periods of time • Amorolfine nail lacquer efficient penetration

19. Pig hoof horn 1.8% of the applied dose is delivered into the nail bed in 7 days (500 µg/cm²) Provedpermeation Amorolfine nail lacquer Penetrationstudies Pittrof F et al. Clin Exp Dermatol, 1992

20. Human nails After 24 hours, the amorolfine concentration in the nail is already above the minimal inhibitory concentration of most fungi causing onychomycosis. Proved penetration Amorolfine nail lacquer Penetrationstudies Polak A., Mycoses ,1993 Franz T.J, Dermatology, 1992

21. Diseased nails 1,2 Antifungal activity in subungual material for up to 7 (1)-14 (2)days after application Proved penetration Supports once weekly regimen Amorolfine nail lacquer Penetrationstudies Mensing H et al., Revista Iberica de Micologia, 1988. Mensing H et al., Clin Exp Dermatol, 1992 

22. Amorolfine nail lacquer Penetration highlights Penetration into the nail platePenetration through the horny tissue into the nail bed Anti-mycotic concentration in the nail bed for at least 7 days More rapid penetration and higher concentrations than oral terbinafine and itraconazole therapies Polak A., Mycoses ,1993

23. Amorolfine nail lacquer PK study

24. Pharmacokinetic study in 20 patients with onychomycosis Maximal clinical dose of amorolfine applied twice weekly for 3 months to all nails (phase I) Then, same dosage regimen only to affected nails for 9 additional months (phase II) • Plasma levels were not measurable in half of the patients and were low (between 0.1 and 0.5 ng/mL) in the other half • No difference between phase I and phase II • No apparent accumulation during either maximal use or therapeutic use Mistry GC., Research Report N-132’521 1994

25. Pharmacokinetic study in patients with onychomycosis Amorolfine applied once or twice weekly for up to 13 months during a phase III study In the 19 tested patients, plasma levels were below the quantification limit of 0.5 ng/mL Roncari G., Research Report B-155’051 1989