|Systematic (IUPAC) name|
|Licence data||EMA:, US FDA:|
|Oral and topical|
|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.|
|CAS Registry Number|
|Molecular mass||348.478 g/mol|
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 1
- Contraindications 2
- Adverse effects 3
- Interactions 4
- Mechanism 5
- Physical properties 6
- History 7
- References 8
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).
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
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.
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 reduce bexarotene's plasma concentrations, hence potentially also mitigating its therapeutic effects.
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.
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.
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.
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.
- Gniadecki, R; Assaf, C; Bagot, M; Dummer, R; Duvic, M; Knobler, R; Ranki, A; Schwandt, P; Whittaker, S (2007). "The optimal use of bexarotene in cutaneous T-cell lymphoma". British Journal of Dermatology 157 (3): 433–40.
- "TARGRETIN (BEXAROTENE) CAPSULE [CARDINAL HEALTH]". DailyMed. Cardinal Health. March 2006. Retrieved 12 January 2014.
- Dragnev, KH; Petty, WJ; Shah, SJ; Lewis, LD; Black, CC; Memoli, V; Nugent, WC; Hermann, T; Negro-Vilar, A; Rigas, JR; Dmitrovsky, E (2007). "A proof-of-principle clinical trial of bexarotene in patients with non-small cell lung cancer" (PDF). Clinical Cancer Research 13 (6): 1794–800.
- Esteva, FJ; Glaspy, J; Baidas, S; Laufman, L; Hutchins, L; Dickler, M; Tripathy, D; Cohen, R; DeMichele, A; Yocum, RC; Osborne, CK; Hayes, DF; Hortobagyi, GN; Winer, E; Demetri, GD (March 2003). "Multicenter Phase II Study of Oral Bexarotene for Patients With Metastatic Breast Cancer" (PDF). Journal of Clinical Oncology 21 (6): 999–1006.
- "Targretin Capsules - Summary of Product Characteristics". electronic Medicines Compendium. Eisai Ltd. 4 April 2013. Retrieved 14 January 2014.
- Brunton, L; Chabner, B; Knollman, B (2010).
- "Targretin (bexarotene) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 31 January 2014.
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- Dawson, M. I.; Xia, Z. (2012). "The retinoid X receptors and their ligands". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1821 (1): 21–56.
- Qu, L; Tang, X (January 2010). "Bexarotene: a promising anticancer agent". Cancer Chemotherapy Pharmacology 65 (2): 201–205.
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- "Lymphoma Treatment: Targretin® (bexarotene)". Timeline of Innovation.
- Vinluan, Frank (2011-10-12). "Generic cancer drug from Banner aims to take on Eisai's Targretin". MedCity News. Retrieved 2012-02-11.
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- "Targretin : EPAR - Product Information" (PDF). European Medicines Agency. Eisai Ltd. 3 April 2013. Retrieved 12 January 2014.
- Cramer, P. E.; Cirrito, J. R.; Wesson, D. W.; Lee, C. Y. D.; Karlo, J. C.; Zinn, A. E.; Casali, B. T.; Restivo, J. L.; et al. (2012). "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models". Science 335 (6075): 1503–1506.
- MedicalXpress (9 February 2012). "FDA-approved drug rapidly clears amyloid from the brain, reverses Alzheimer's symptoms in mice". MedicalXpress. Retrieved 14 February 2012.
- Fitz, N. F.; Cronican, A. A.; Lefterov, I.; Koldamova, R. (2013). "Comment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"". Science 340 (6135): 924.
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- Tesseur, I.; Lo, A. C.; Roberfroid, A.; Dietvorst, S.; Van Broeck, B.; Borgers, M.; Gijsen, H.; Moechars, D.; et al. (2013). "Comment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"". Science 340 (6135): 924.
- Veeraraghavalu, K.; Zhang, C.; Miller, S.; Hefendehl, J. K.; Rajapaksha, T. W.; Ulrich, J.; Jucker, M.; Holtzman, D. M.; et al. (2013). "Comment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"". Science 340 (6135): 924.
- "Anti-Cancer Drug Reverses Alzheimer's Disease In Mice". Medical News Today. 25 May 2013.