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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.
After oral administration of Targretin® capsules, bexarotene is absorbed with a Tmax of
about two hours. Terminal half-life of bexarotene is about seven hours. Studies in patients with advanced malignancies show approximate single dose linearity within the therapeutic range and low accumulation with multiple doses. Plasma bexarotene AUC and Cmax values resulting from a 300 mg dose were 35% and 48% higher, respectively, after a fat-containing meal than after a glucose solution (see PRECAUTIONS: Drug-Food Interaction and DOSAGE AND ADMINISTRATION). 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: 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® (bexarotene) capsules is unknown.
The renal elimination of bexarotene and its metabolites was examined in patients with Type 2 diabetes mellitus. Neither bexarotene nor its metabolites were excreted in urine in appreciable amounts. Bexarotene is thought to be eliminated primarily through the hepatobiliary system.
Elderly: Bexarotene Cmax and AUC were similar in advanced cancer patients <60 years old and in patients >60 years old, including a subset of patients >70 years old.
Pediatric: Studies to evaluate bexarotene pharmacokinetics in the pediatric population have not been conducted (see PRECAUTIONS: Pediatric Use).
Gender: The pharmacokinetics of bexarotene were similar in male and female patients with advanced cancer.
Ethnic Origin: The effect of ethnic origin on bexarotene pharmacokinetics is unknown.
Renal Insufficiency: No formal studies have been conducted with Targretin® (bexarotene) capsules in patients with renal insufficiency. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of 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® (bexarotene) capsules in patients with hepatic insufficiency. Because less than 1% of the dose 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 WARNINGS: Hepatic Insufficiency).
No specific studies to evaluate drug interactions with bexarotene have been conducted. Bexarotene oxidative metabolites appear to be formed by cytochrome P450 3A4.
Because bexarotene is metabolized by cytochrome P450 3A4, ketoconazole, itraconazole, erythromycin, gemfibrozil, grapefruit juice, and other inhibitors of cytochrome P450 3A4 would be expected to lead to an increase in plasma bexarotene concentrations. Furthermore, rifampin, phenytoin, phenobarbital and other inducers of cytochrome P450 3A4 may cause a reduction in plasma bexarotene concentrations.
Concomitant administration of Targretin® (bexarotene) capsules and gemfibrozil resulted in substantial increases in plasma concentrations of bexarotene, probably at least partially related to cytochrome P450 3A4 inhibition by gemfibrozil. Under similar conditions, bexarotene concentrations were not affected by concomitant atorvastatin administration. Concomitant administration of gemfibrozil with Targretin® (bexarotene) capsules is not recommended (see PRECAUTIONS: Drug-Drug Interactions).
Based on interim data, concomitant administration of Targretin® (bexarotene) capsules and tamoxifen resulted in approximately a 35% decrease in plasma concentrations of tamoxifen, possibly through an induction of cytochrome P450 3A4. Based on this known interaction, bexarotene may theoretically increase the rate of metabolism and reduce plasma concentrations of other substrates metabolized by cytochrome P450, including oral or other systemic hormonal contraceptives (see CONTRAINDICATIONS: Pregnancy: Category X and PRECAUTIONS: Drug-Drug Interactions).
Targretin® (bexarotene) capsules were evaluated in 152 patients with advanced and early stage cutaneous T-cell lymphoma (CTCL) in two multicenter, open-label, historically-controlled clinical studies conducted in the U.S., Canada, Europe, and Australia.
The advanced disease patients had disease refractory to at least one prior systemic therapy (median of two, range one to six prior systemic therapies) and had been treated with a median of five (range 1 to 11) prior systemic, irradiation, and/or topical therapies. Early disease patients were intolerant to, had disease that was refractory to, or had reached a response plateau of six months on, at least two prior therapies. The patients entered had been treated with a median of 3.5 (range 2 to 12) therapies (systemic, radiation, and/or topical).
The two clinical studies enrolled a total of 152 patients, 102 of whom had disease refractory to at least one prior systemic therapy, 90 with advanced disease and 12 with early disease. This is the patient population for whom Targretin® (bexarotene) capsules are indicated.
Patients were initially treated with a starting dose of 650 mg/m2/day with a subsequent reduction of starting dose to 500 mg/m2/day. Neither of these starting doses was tolerated, and the starting dose was then reduced to 300 mg/m2/day. If, however, a patient on 300 mg/m2/day of Targretin® (bexarotene) capsules showed no response after eight or more weeks of therapy, the dose could be increased to 400 mg/m2/day.
Tumor response was assessed in both studies 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. Also considered in response assessment was the presence or absence of cutaneous tumors and extracutaneous disease manifestations.
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 without worsening, or development of new cutaneous tumors or non-cutaneous manifestations. A complete clinical response required complete disappearance of all manifestations of disease, but did not require confirmation by biopsy.
At the initial dose of 300 mg/m2/day, 1/62 (1.6%) of patients had a complete clinical tumor response and 19/62 (30%) of patients had a partial tumor response. The rate of relapse (25% increase in CA or worsening of other aspects of disease) in the 20 patients who had a tumor response was 6/20 (30%) over a median duration of observation of 21 weeks, and the median duration of tumor response had not been reached. Responses were seen as early as 4 weeks and new responses continued to be seen at later visits.
Last reviewed on RxList: 9/19/2008
This monograph has been modified to include the generic and brand name in many instances.
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