CLINICAL PHARMACOLOGY
Tazarotene is a retinoid prodrug which is converted to its active
form, the cognate carboxylic acid of tazarotene (AGN 190299), by rapid
deesterification in animals and man. AGN 190299 (“tazarotenic acid”) binds to
all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and
RARγ but shows relative selectivity for RARβ, and RARγ and may modify gene
expression. The clinical significance of these findings is unknown.
Psoriasis: The mechanism of tazarotene
action in psoriasis is not defined. Topical tazarotene blocks induction of mouse
epidermal ornithine decarboxylase (ODC) activity, which is associated with cell
proliferation and hyperplasia. In cell culture and in
vitro models of skin, tazarotene suppresses expression of MRP8, a marker
of inflammation present in the epidermis of psoriasis patients at high levels.
In human keratinocyte cultures, it inhibits cornified envelope formation, whose
build-up is an element of the psoriatic scale. Tazarotene also induces the
expression of a gene which may be a growth suppressor in human keratinocytes and
which may inhibit epidermal hyperproliferation in treated plaques. However, the
clinical significance of these findings is unknown.
Acne: The mechanism of tazarotene action
in acne vulgaris is not defined. However, the basis of tazarotene's therapeutic
effect in acne may be due to its anti-hyperproliferative,
normalizing-of-differentiation and anti-inflammatory effects. Tazarotene
inhibited corneocyte accumulation in rhino mouse skin and cross-linked envelope
formation in cultured human keratinocytes. The clinical significance of these
findings is unknown.
Pharmacokinetics:
Following topical application, tazarotene undergoes esterase
hydrolysis to form its active metabolite, tazarotenic acid. Little parent
compound could be detected in the plasma. Tazarotenic acid was highly bound to
plasma proteins (>99%). Tazarotene and tazarotenic acid were metabolized to
sulfoxides, sulfones and other polar metabolites which were eliminated through
urinary and fecal pathways. The half-life of tazarotenic acid was approximately
18 hours, following topical application of tazarotene to normal, acne or
psoriatic skin.
The human in vivo studies described below were
conducted with tazarotene gel applied topically at approximately 2 mg/cm2 and left on the skin for 10 to 12 hours. Both the peak plasma
concentration (Cmax) and area under the plasma concentration time curve (AUC)
refer to the active metabolite only.
Two single, topical dose studies were conducted using 14C-tazarotene gel. Systemic absorption, as determined from
radioactivity in the excreta, was less than 1% of the applied dose (without
occlusion) in six psoriatic patients and approximately 5% of the applied dose
(under occlusion) in six healthy subjects. One non-radiolabeled single-dose
study comparing the 0.05% gel to the 0.1% gel in healthy subjects indicated that
the Cmax and AUC were 40% higher for the 0.1% gel.
After 7 days of topical dosing with measured doses of tazarotene 0.1% gel on
20% of the total body surface without occlusion in 24 healthy subjects, the Cmax
for tazarotenic acid was 0.72 ± 0.58 ng/mL (mean ± SD) occurring 9 hours after
the last dose, and the AUC0-24hr for tazarotenic acid was
10.1 ± 7.2 ng·hr/mL. Systemic absorption was 0.91 ± 0.67% of the applied
dose.
In a 14-day study in five psoriatic patients, measured doses of tazarotene
0.1% gel were applied daily by nursing staff to involved skin without occlusion
(8 to 18% of total body surface area; mean ± SD: 13 ± 5%). The Cmax for
tazarotenic acid was 12.0 ± 7.6 ng/mL occurring 6 hours after the final dose,
and the AUC0-24hr for tazarotenic acid was
105 ± 55 ng·hr/mL. Systemic absorption was 14.8 ± 7.6% of the applied dose.
Extrapolation of these results to represent dosing on 20% of total body surface
yielded estimates for tazarotenic acid with Cmax of 18.9 ± 10.6 ng/mL and
AUC0-24hr of 172 ± 88 ng·hr/mL.
An in vitro percutaneous absorption study, using
radiolabeled drug and freshly excised human skin or human cadaver skin,
indicated that approximately 4 to 5% of the applied dose was in the stratum
corneum (tazarotene: tazarotenic acid= 5:1) and 2 to 4% was in the viable
epidermis-dermis layer (tazarotene: tazarotenic acid= 2:1) 24 hours after
topical application of the gel.
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