Targretin

TARGRETIN- bexarotene gel
Ligand Pharmaceuticals Inc.

DESCRIPTION

Targretin® (bexarotene) gel 1% contains bexarotene and is intended for topical application only. Bexarotene is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs).

The chemical name is 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl] benzoic acid, and the structural formula is as follows:

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Bexarotene is an off-white to white powder with a molecular weight of 348.48 and a molecular formula of C24 H28 O2 . It is insoluble in water and slightly soluble in vegetable oils and ethanol, USP.

Targretin® gel is a clear gelled solution containing 1.0% (w/w) bexarotene in a base of dehydrated alcohol, USP, polyethylene glycol 400, NF, hydroxypropyl cellulose, NF, and butylated hydroxytoluene, NF.

CLINICAL PHARMACOLOGY

Mechanism of Action

Bexarotene selectively binds and activates retinoid X receptor subtypes (RXRα, RXRβ, RXRγ). RXRs can form heterodimers with various receptor partners such as retinoic acid receptors (RARs), vitamin D receptor, thyroid receptor, and peroxisome proliferator activator receptors (PPARs). Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin. It also induces tumor regression in vivo in some animal models. The exact mechanism of action of bexarotene in the treatment of cutaneous T-cell lymphoma (CTCL) is unknown.

Pharmacokinetics

General

Plasma concentrations of bexarotene were determined during clinical studies in patients with CTCL or following repeated single or multiple-daily dose applications of Targretin® gel 1% for up to 132 weeks. Plasma bexarotene concentrations were generally less than 5 ng/mL and did not exceed 55 ng/mL. However, only two patients with very intense dosing regimens (> 40% BSA lesions and QID dosing) were sampled. Plasma bexarotene concentrations and the frequency of detecting quantifiable plasma bexarotene concentrations increased with increasing percent body surface area treated and increasing quantity of Targretin® gel applied. The sporadically-observed and generally low plasma bexarotene concentrations indicated that, in patients receiving doses of low to moderate intensity, there is a low potential for significant plasma concentrations following repeated application of Targretin® gel. Bexarotene is highly bound (>99%) to plasma proteins. The plasma proteins to which bexarotene binds have not been elucidated, and the ability of bexarotene to displace drugs bound to plasma proteins and the ability of drugs to displace bexarotene binding have not been studied (see PRECAUTIONS: Protein Binding). The uptake of bexarotene by organs or tissues has not been evaluated.

Metabolism

Four bexarotene metabolites have been identified in plasma following oral administration of bexarotene: 6- and 7-hydroxy-bexarotene and 6- and 7-oxo-bexarotene. In vitro studies suggest that cytochrome P450 3A4 is the major cytochrome P450 responsible for formation of the oxidative metabolites and that the oxidative metabolites may be glucuronidated. The oxidative metabolites are active in in vitro assays of retinoid receptor activation, but the relative contribution of the parent and any metabolites to the efficacy and safety of Targretin® gel is unknown.

Elimination

The renal elimination of bexarotene and its metabolites was examined in patients with Type 2 diabetes mellitus following oral administration of bexarotene. Neither bexarotene nor its metabolites were excreted in urine in appreciable amounts.

Special Populations

Elderly, Gender, Race: Because of a large number of immeasurable plasma concentrations (< 1ng/mL), any potential pharmacokinetic differences between Special Populations could not be assessed.

Pediatric: Studies to evaluate bexarotene pharmacokinetics in the pediatric population have not been conducted (see PRECAUTIONS: Pediatric Use).

Renal Insufficiency: No formal studies have been conducted with Targretin® gel in patients with renal insufficiency. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of an orally administered dose), but because renal insufficiency can result in significant protein binding changes, pharmacokinetics may be altered in patients with renal insufficiency (see PRECAUTIONS: Renal Insufficiency).

Hepatic Insufficiency: No specific studies have been conducted with Targretin® gel in patients with hepatic insufficiency. Because less than 1% of the dose of oral bexarotene is excreted in the urine unchanged and there is in vitro evidence of extensive hepatic contribution to bexarotene elimination, hepatic impairment would be expected to lead to greatly decreased clearance (see PRECAUTIONS: Hepatic Insufficiency).

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