Chemistry:Bexarotene

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Short description: Chemical compound
Bexarotene
Bexarotene2DACS.svg
Bexarotene3Dan.gif
Clinical data
Trade namesTargretin
AHFS/Drugs.comMonograph
MedlinePlusa608006
License data
Routes of
administration		By mouth, topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding>99%
MetabolismHepatic (CYP3A4-mediated)
Elimination half-life7 hours
ExcretionParent drug and metabolites are eliminated primarily through the hepatobiliary system. Less than 1% is excreted in the urine unchanged.
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC24H28O2
Molar mass348.486 g·mol−1
3D model (JSmol)
  (verify)

Bexarotene, sold under the brand Targretin, is an antineoplastic (anti-cancer) agent used for the treatment of cutaneous T cell lymphoma (CTCL).[2] It is a third-generation retinoid.[3]

It was approved by the U.S. Food and Drug Administration (FDA) in December 1999, and the European Medicines Agency (EMA) in March 2001. It is available as a generic medication.[4][5]

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).[1]

It has been used off-label for non-small cell lung cancer[6] and breast cancer.[7]

Contraindications

Known contraindications include:[8]

  • 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, hypothyroidism.[1][8][9][10]

Interactions

Its plasma concentration may be increased by concomitant treatment with CYP3A4 inhibitors such as ketoconazole.[8] It may also induce CYP3A4, and hence CYP3A4 substrates like cyclophosphamide may have their plasma concentrations reduced.[8] Likewise consumption of grapefruit juice might increase bexarotene's plasma concentrations, hence potentially altering its therapeutic effects.[8]

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).[10][11][12] By so doing it induces cell differentiation and apoptosis and prevents the development of drug resistance.[13] It also has anti-angiogenic effects and inhibits cancer metastasis.[13] The retinoic acid receptors (RARs) regulate cell differentiation and proliferation whereas RXRs regulate apoptosis.[9]

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.[14]

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.[15]

The developer of bexarotene (brand name Targretin) was Ligand Pharmaceuticals, a San Diego biotech company which received FDA approval for the drug in 1999.[16] The FDA approved bexarotene on 29 December 1999.[17]

Japanese pharmaceutical Eisai bought the rights to Targretin and three other anti-cancer products from Ligand in 2006.[16] In the United States, patents on the drug expired in 2016.[16]

It received EMA approval on 29 March 2001.[18]

Early-stage preclinical studies suggested that bexarotene reduced amyloid plaques and improved mental functioning in a small sample of mice engineered to exhibit Alzheimer's-like symptoms[19][20] although subsequent studies have yielded mixed results.[21][22][23][24][25]

The results of CCMR-One, a clinical trial of the effects of bexarotene on patients with multiple sclerosis operated by the University of Cambridge,[26] have shown that the drug can cause remyelination, but will not lead to the drug being used as a therapy, due to its risk profile.[27]

References

  1. ↑ 1.0 1.1 1.2 "TARGRETIN (BEXAROTENE) CAPSULE [CARDINAL HEALTH"]. DailyMed. Cardinal Health. March 2006. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=63656f64-e240-4855-8df9-ca1655863735. 
  2. ↑ "The optimal use of bexarotene in cutaneous T-cell lymphoma". The British Journal of Dermatology 157 (3): 433–440. September 2007. doi:10.1111/j.1365-2133.2007.07975.x. PMID 17553039. 
  3. ↑ "Discovery of the FDA-approved drugs bexarotene, cetilistat, diiodohydroxyquinoline, and abiraterone as potential COVID-19 treatments with a robust two-tier screening system". Pharmacological Research 159: 104960. September 2020. doi:10.1016/j.phrs.2020.104960. PMID 32473310. 
  4. ↑ "2022 First Generic Drug Approvals". 3 March 2023. https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals. 
  5. ↑ "Competitive Generic Therapy Approvals". 3 March 2023. https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals. 
  6. ↑ "A proof-of-principle clinical trial of bexarotene in patients with non-small cell lung cancer". Clinical Cancer Research 13 (6): 1794–1800. March 2007. doi:10.1158/1078-0432.CCR-06-1836. PMID 17363535. https://aacr.figshare.com/articles/journal_contribution/Supplementary_Data_from_A_Proof-of-Principle_Clinical_Trial_of_Bexarotene_in_Patients_with_Non_Small_Cell_Lung_Cancer/22441278/1/files/39892149.pdf. 
  7. ↑ "Multicenter phase II study of oral bexarotene for patients with metastatic breast cancer". Journal of Clinical Oncology 21 (6): 999–1006. March 2003. doi:10.1200/JCO.2003.05.068. PMID 12637463. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 "Targretin Capsules - Summary of Product Characteristics". electronic Medicines Compendium. Eisai Ltd. 4 April 2013. http://www.medicines.org.uk/emc/medicine/26618/SPC/Targretin+Capsules/. 
  9. ↑ 9.0 9.1 Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. 2010. ISBN 978-0-07-162442-8. 
  10. ↑ 10.0 10.1 "Targretin (bexarotene) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/targretin-bexarotene-342234#showall. 
  11. ↑ "Retinoid X receptors". The International Journal of Biochemistry & Cell Biology 29 (2): 275–278. February 1997. doi:10.1016/S1357-2725(96)00101-X. PMID 9147128. 
  12. ↑ "The retinoid X receptors and their ligands". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1821 (1): 21–56. January 2012. doi:10.1016/j.bbalip.2011.09.014. PMID 22020178. 
  13. ↑ 13.0 13.1 "Bexarotene: a promising anticancer agent". Cancer Chemotherapy and Pharmacology 65 (2): 201–205. January 2010. doi:10.1007/s00280-009-1140-4. PMID 19777233. 
  14. ↑ "Bexarotene MSDS". LC Labs. http://www.lclabs.com/printableMSDS/B-2422MSDSprintable.html. 
  15. ↑ "Lymphoma Treatment: Targretin (bexarotene)". Timeline of Innovation. SRI International. http://www.sri.com/work/timeline-innovation/timeline.php?timeline=health#!&innovation=targretin. 
  16. ↑ 16.0 16.1 16.2 "Generic cancer drug from Banner aims to take on Eisai's Targretin". MedCity News. 12 October 2011. http://www.medcitynews.com/2011/10/generic-cancer-drug-from-banner-aims-to-take-on-eisais-targretin/. 
  17. ↑ "Bexarotene". Drugs.com. https://www.drugs.com/ppa/bexarotene.html. 
  18. ↑ "Targretin : EPAR - Product Information". European Medicines Agency. Eisai Ltd. 3 April 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000326/WC500034208.pdf. 
  19. ↑ "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science 335 (6075): 1503–1506. March 2012. doi:10.1126/science.1217697. PMID 22323736. Bibcode: 2012Sci...335.1503C. 
  20. ↑ MedicalXpress (9 February 2012). "FDA-approved drug rapidly clears amyloid from the brain, reverses Alzheimer's symptoms in mice". http://medicalxpress.com/news/2012-02-fda-approved-drug-rapidly-amyloid-brain.html. 
  21. ↑ "Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models"". Science 340 (6135): 924–92c. May 2013. doi:10.1126/science.1235809. PMID 23704552. Bibcode: 2013Sci...340..924F. 
  22. ↑ "Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models"". Science 340 (6135): 924–92d. May 2013. doi:10.1126/science.1234089. PMID 23704553. Bibcode: 2013Sci...340..924P. 
  23. ↑ "Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models"". Science 340 (6135): 924–92e. May 2013. doi:10.1126/science.1233937. PMID 23704554. Bibcode: 2013Sci...340R.924T. 
  24. ↑ "Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models"". Science 340 (6135): 924–92f. May 2013. doi:10.1126/science.1235505. PMID 23704555. Bibcode: 2013Sci...340..924V. 
  25. ↑ "Anti-Cancer Drug Reverses Alzheimer's Disease In Mice". Medical News Today. 25 May 2013. http://www.medicalnewstoday.com/articles/261025.php. 
  26. ↑ "Trials in Cambridge" (in en-GB). https://www-neurosciences.medschl.cam.ac.uk/jones-coles-group/trials-in-cambridge/. 
  27. ↑ "MS treatment a step closer after drug shown to repair nerve coating" (in en). 25 September 2020. http://www.theguardian.com/society/2020/sep/25/ms-treatment-step-closer-drug-shown-to-repair-nerve-coating-trial-multiple-sclerosis. 

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