e chemical name for halobetasol propionate is [(6S,9R,16S,17R)-17-(2-chloroacetyl)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]propanoate. The structural formula for halobetasol propionate is represented below:
Molecular Formula: C25H31ClF2O5 Molecular Weight: 484.96
Tazarotene is a member of the acetylenic class of retinoids. The chemical name for tazarotene is 6-[(3,4-Dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)ethynyl]-3-pyridinecarboxylic acid ethyl ester. The structural formula for tazarotene is represented below:
Tazarotene:
Molecular Formula: C21H21NO2S Molecular Weight: 351.46
Each gram of DUOBRII Lotion contains 0.1 mg (0.01%) halobetasol propionate and 0.45 mg (0.045%) tazarotene in a white to offwhitelotion base consisting of carbomer copolymer type B, carbomer homopolymer type A, diethyl sebacate, edetate disodiumdihydrate, light mineral oil, methylparaben, propylparaben, purified water, sodium hydroxide, sorbitan monooleate and sorbitolsolution, 70%.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precisemechanism of action in plaque psoriasis is unknown.
Tazarotene is a retinoid prodrug which is converted to its active form, tazarotenic acid, the carboxylic acid of tazarotene, bydeesterification. Tazarotenic acid binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ and RARγ, butshows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings for thetreatment of plaque psoriasis is unknown.
12.2 Pharmacodynamics
A vasoconstrictor assay in healthy subjects with DUOBRII Lotion indicated that it is in the high to super-high range of potency ascompared to other topical corticosteroids; however, similar blanching scores do not necessarily imply therapeutic equivalence.
The potential for hypothalamic-pituitary-adrenal (HPA) axis suppression was eva luated in a study in adult subjects with moderate tosevere plaque psoriasis. A median dose of 8.2 grams DUOBRII Lotion was applied once daily for 8 weeks and 20 subjects wereassessed for HPA axis suppression at Weeks 4 and 8. HPA axis suppression was observed in 3 out of 20 (15%) subjects at Week 4.None of the 20 (0%) subjects had HPA axis suppression at Week 8. In this study, the criteria for HPA axis suppression was a serumcortisol level of less than or equal to 18 micrograms per deciliter 30 minutes after stimulation with cosyntropin (adrenocorticotropichormone). [See Warnings and Precautions (5.2).]
The pharmacodynamics of tazarotene is unknown.
12.3 Pharmacokinetics
Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid.
Systemic exposure following topical application of DUOBRII Lotion was eva luated in the same study that eva luated the HPA axissuppression. It was an open-label, randomized, pharmacokinetics (PK) study conducted in subjects aged 18 years and older withmoderate to severe plaque psoriasis affecting at least 20% body surface area. The PK of halobetasol propionate, tazarotene, andtazarotenic acid was eva luated in 22 subjects following application of DUOBRII Lotion to the affected area once daily for 28 days. |
