Bexarotene

Bexarotene

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Systematic (IUPAC) name
4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoic acid
Clinical data
Trade names	Targretin
AHFS/Drugs.com	monograph
MedlinePlus	a608006
Licence data	EMA:Link, US FDA:link
Pregnancy category	US: X (Contraindicated)
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral and topical
Pharmacokinetic data
Protein binding	>99%
Metabolism	Hepatic (CYP3A4-mediated)
Biological half-life	7 hours
Excretion	Parent drug and metabolites are eliminated primarily through the hepatobiliary system. Less than 1% is excreted in the urine unchanged.
Identifiers
CAS Number	153559-49-0 Y
ATC code	L01XX25 (WHO)
PubChem	CID: 82146
IUPHAR/BPS	2807
DrugBank	DB00307 Y
ChemSpider	74139 Y
UNII	A61RXM4375 Y
ChEBI	CHEBI:50859 Y
ChEMBL	CHEMBL1023 Y
Chemical data
Formula	C24H28O2
Molecular mass	348.478 g/mol
SMILES O=C(O)c1ccc(cc1)C(/c2c(cc3c(c2)C(CCC3(C)C)(C)C)C)=C
InChI InChI=1S/C24H28O2/c1-15-13-20-21(24(5,6)12-11-23(20,3)4)14-19(15)16(2)17-7-9-18(10-8-17)22(25)26/h7-10,13-14H,2,11-12H2,1,3-6H3,(H,25,26) Y Key:NAVMQTYZDKMPEU-UHFFFAOYSA-N Y
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Bexarotene (brand name: Targretin) is an antineoplastic (anti-cancer) agent approved by the U.S.Food and Drug Administration (FDA) (in late 1999) and the European Medicines Agency (EMA) (early 2001) for use as a treatment for cutaneous T cell lymphoma (CTCL). It is a third-generation retinoid.

Medical uses

Bexarotene is indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in people who are refractory to at least one prior systemic therapy (oral) and for the topical treatment of cutaneous lesions in patients with CTCL who have refractory or persistent disease after other therapies or who have not tolerated other therapies (topical).

It has been used off-label for non-small cell lung cancer and breast cancer.

Contraindications

Known contraindications include:

• Hypersensitivity to the active substance or to any of the excipients in the preparation(s).
• Pregnancy and lactation
• Women of child-bearing potential without effective birth-control measures
• History of pancreatitis
• Uncontrolled hypercholesterolaemia
• Uncontrolled hypertriglyceridaemia
• Hypervitaminosis A
• Uncontrolled thyroid disease
• Hepatic insufficiency
• Ongoing systemic infection

Adverse effects

Overall the most common adverse effects are skin reactions (mostly itchiness and rashes), leucopenia, headache, weakness, thyroid anomalies (which seem to be mediated by RXR-mediated downregulation of thyroid stimulating hormone) and blood lipid anomalies such as hypercholesterolaemia (high blood cholesterol) and hyperlipidaemia.

Interactions

Its plasma concentration may be increased by concomitant treatment with CYP3A4 inhibitors such as ketoconazole. It may also induce CYP3A4, and hence CYP3A4 substrates like cyclophosphamide may have their plasma concentrations reduced. Likewise consumption of grapefruit juice might increase bexarotene's plasma concentrations, hence potentially altering its therapeutic effects.

Mechanism

Bexarotene is a retinoid that selectively activates retinoid X receptors (RXRs), as opposed to the retinoic acid receptors, the other major target of retinoic acid (the acid form of vitamin A). By so doing it induces cell differentiation and apoptosis and prevents the development of drug resistance. It also has anti-angiogenic effects and inhibits cancer metastasis. The retinoic acid receptors (RARs) regulate cell differentiation and proliferation whereas RXRs regulate apoptosis.

Physical properties

Bexarotene is a solid, white powder. It is poorly soluble in water; the solubility is estimated to be about 10-50 µM. It is soluble in DMSO at 65 mg/mL and in ethanol at 10 mg/mL with warming.

History

SRI International and the La Jolla Cancer Research Foundation (now the Sanford-Burnham Medical Research Institute) collaborated on work that resulted in patent filings for the drug.

The developer of bexarotene (brand name Targretin) was Ligand Pharmaceuticals, a San Diego biotech company which received FDA approval for the drug in 1999. The FDA approved bexarotene on the 29th December 1999.

Japanese pharmaceutical Eisai bought the rights to Targretin and three other anti-cancer products from Ligand in 2006. In the United States, patents on the drug expire in 2016.

It received EMA approval on the 29th of March 2001.

In 2012 and 2013, bexarotene researchers reported that bexarotene reduced amyloid plaque and improved mental functioning in a small sample of mice engineered to exhibit Alzheimer's-like symptoms and the findings were promoted in the media. In 2013, several research groups reported on their attempts to reproduce these findings. The results were mixed: none of the studies found a reduction in amyloid plaques, but several of the studies found that soluble forms of β-amyloid were reduced.