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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.
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.
Four bexarotene metabolites have been identified in plasma following oral administration of bexarotene: 6- and 7-hydroxy-bexarotene and 6- and 7-oxobexarotene. 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.
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.
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).
No formal studies to evaluate drug interactions with bexarotene or Targretin® gel have been conducted. Bexarotene oxidative metabolites appear to be formed through cytochrome P450 3A4. Drugs that affect levels or activity of cytochrome P450 3A4 may potentially affect the disposition of bexarotene. Concomitant gemfibrozil was associated with increased bexarotene concentrations following oral administration of bexarotene.
Targretin® gel was evaluated for the treatment of patients with early stage (Stage IA-IIA) CTCL in one multicenter, open-label, clinical trial as well as in a Phase I-II program (dose-seeking trials with different response criteria than the multicenter trial). These clinical studies enrolled a total of 117 patients.
In the multicenter, open-label clinical trial, Targretin® gel was evaluated for the treatment of patients with early stage CTCL who were refractory to, intolerant to, or reached a response plateau for at least six months on at least two prior therapies. The study was conducted in the U.S., Canada, Europe, and Australia and enrolled a total of 50 patients; 46% of these patients were male, 80% were Caucasian, and the median age was 64 years (range 13 to 85).
Targretin® gel was also evaluated for the treatment of patients with CTCL in a U.S. Phase I-II program involving patients with early stage CTCL. This program enrolled a total of 67 patients; 55% of these patients were male, 85% were Caucasian, and the median age was 61 years (range 30 to 87).
In the multicenter, open-label clinical trial, considering prior systemic, irradiation, and topical treatments, patients had been exposed to a median of three prior therapies (range 2-7). All patients failed at least two treatments; the majority (68%) of patients were either refractory to two or more therapies or were refractory to one therapy and intolerant to at least one therapy.
Patients were treated with Targretin® gel 1% for a planned 16-week period with an option to continue provided that no unacceptable toxicity was occurring.
Tumor response was assessed in the multicenter study by observation of up to five baseline-defined index lesions using a Composite Assessment of Index Lesion Disease Severity (CA). This endpoint was based on a summation of the grades, for all index lesions, of erythema, scaling, plaque elevation, hypopigmentation or hyperpigmentation, and area of involvement. New cutaneous lesions or tumors and extracutaneous disease manifestations were not considered in response or disease progression assessments.
All tumor responses required confirmation over at least two assessments separated by at least four weeks. A partial response was defined as an improvement of at least 50% in the index lesions. A complete clinical response required complete disappearance of the index lesions, but did not require confirmation by biopsy.
Targretin® gel produced an overall response rate of 26% (13/50) with a corresponding exact 95% confidence interval from 14.6% to 40.3% by the Composite Assessment of Index Lesion Severity. For the Stage IA and IB patients, the response rate was 28% (13/47) with a corresponding exact 95% confidence interval from 15.6% to 42.6%. For the Stage II patients the response rate was 0% (0/3). Two percent of patients (1/50) had a clinical complete response. The median time to best response on the Composite Assessment of Index Lesion Severity (n=13) was 85 days (range: 36-154).
The rate of relapse in responding patients by the Composite Assessment of Index Lesion Severity was 23% (3/13) over a median observation period of 149 days (range 56-342). Fourteen patients developed new lesions in untreated areas (14/50; 28%). Four patients developed clinically abnormal lymph nodes ( ≥ 1cm diam) (4/50; 8%). One patient developed a cutaneous tumor (1/50; 2%).
The Phase I-II program (dose-seeking trials with different response criteria than the multicenter trial) was supportive of the multicenter study results.
Last reviewed on RxList: 6/2/2011
This monograph has been modified to include the generic and brand name in many instances.
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