Clinical Pharmacokinetics and Drug Metabolism of Tazarotene

Abstract

Tazarotene (AGN 190168) is a new acetylenic retinoid which is effective for the topical treatment of patients with stable plaque psoriasis and mild to moderate acne vulgaris. Topical gel application provides direct delivery of tazarotene into the skin. At 10 hours after a topical application of 0.1% tazarotene gel to the skin of healthy individuals and patients with psoriasis, approximately 4 to 6% of the dose resided in the stratum corneum and 2% of the dose distributed to the viable epidermis and dermis. Tazarotene is rapidly hydrolysed by esterases to its active metabolite, tazarotenic acid. Tazarotenic acid does not accumulate in adipose tissue, but undergoes further metabolism to its sulfoxide and to other polar metabolites and is rapidly eliminated via both urinary and faecal pathways with a terminal half-life of about 18 hours. Percutaneous absorption is similar between healthy individuals and patients with facial acne, leading to plasma concentrations below 1 microg/L. The systemic bioavailability of tazarotene (measured as tazarotenic acid) is low, approximately 1% after single and multiple topical applications to healthy skin. In patients with psoriasis under typical conditions of use, systemic bioavailability increased during the initial 2 weeks of treatment from 1% (single dose) to 5% or less (steady state). The increased bioavailability is probably related to decreases in plaque elevation and scaling due to successful treatment, resulting in a less effective skin penetration barrier to tazarotene. Steady-state concentrations of tazarotenic acid are achieved within 2 weeks of topical treatment in both healthy and psoriatic skin types. The large variability in plasma concentrations observed in patients with psoriasis is probably because of the large differences in lesional skin condition, the amount of drug applied and the surface area of application. There was no significant drug accumulation in the body with long term treatment of patients with psoriasis. Topical administration of tazarotene requires dosages much smaller than those usually required for oral retinoids, such as isotretinoin, acitretin and etretinate, and it delivers the drug directly into the target skin tissues. The low systemic absorption and rapid systemic elimination of tazarotene and tazarotenic acid results in limited systemic exposure. Thus, topical tazarotene has a low potential for systemic adverse effects and is effective in the treatment of patients with acne and psoriasis.

Suppressed Serum Prolactin Levels under Topical Treatment with Isoretinoin

“…All of these studies mentioned investigated endocrinological effects of oral retinoid treatment. For topical retinoid treatment a low systemic bioavailability (<1%) after a single dose with increasing bioavailability after continuous treatment (up to 5.3%) was shown in a group of patients with psoriasis [8]. Experimental data suggests that percutaneous absorption rate is affected by state of the skin barrier, retinoid type, vehicle and dose [9].…”

Topical Therapies for Psoriasis

“…The systemic availability after topical tazarotene 0.05% or 0.1% gel is < 1% after single application, and 2.6% and 5.3%, respectively, after once-daily applications following 2 weeks of treatment. After 12 weeks of treatment, the systemic availability of tazarotene 0.05% was 1.8% and for the 0.1% tazarotene preparation it was 3.9% (Tang-Liu et al, 1999).…”

Cytochrome P450 2C8 and Flavin-containing Monooxygenases are Involved in the Metabolism of Tazarotenic Acid in Humans

“…Following topical administration of tazarotene to healthy volunteers or patients with psoriasis or acne vulgaris, low but detectable plasma levels of tazarotenic acid can be measured (Tang-Liu et al, 1999). Oral tazarotene is currently in clinical development for the treatment of plaque psoriasis and acne.…”

“…The rapid blood hydrolysis of tazarotene to the more water soluble tazarotenic acid is mediated by one or more paraoxon-inhibitable esterases (Madhu et al, 1997). In rat and human liver microsomes, the biotransformation of tazarotene was independent of cytochrome P450 (Tang-Liu et al, 1999). A recent pharmacokinetic study to assess the safety and dose proportionality of oral tazarotene found the main circulating agent, tazarotenic acid, was rapidly available in the systemic circulation with T max ranging from 2-to 3-h postdose (Tang-Liu et al, 1999).…”

“…A recent pharmacokinetic study to assess the safety and dose proportionality of oral tazarotene found the main circulating agent, tazarotenic acid, was rapidly available in the systemic circulation with T max ranging from 2-to 3-h postdose (Tang-Liu et al, 1999). Tazarotenic acid is subsequently oxidized to the inactive sulfoxide metabolite, the major metabolite excreted in urine (Tang-Liu et al, 1999).…”