Bexarotene

Bexarotene
Names
Trade namesTargretin, others
IUPAC name
  • 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoic acid
Clinical data
Drug classRetinoid[1]
Main usesCutaneous T cell lymphoma (CTCL)[1]
Side effectsBy mouth: High cholesterol, headaches, low thyroid, low white blood cells, rash, nausea, infection, dry skin, peripheral swelling[2]
Topical: Rash, itchiness[3]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth, topical
Typical dose300 mg/m2/day[1]
External links
AHFS/Drugs.comSystemic: Monograph
Topical: Monograph
MedlinePlusa608006
Legal
License data
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetics
Protein binding>99%
MetabolismLiver (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.
Chemical and physical data
FormulaC24H28O2
Molar mass348.486 g·mol−1
3D model (JSmol)
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) checkY
  • Key:NAVMQTYZDKMPEU-UHFFFAOYSA-N checkY

Bexarotene, sold under the brand Targretin among others, is a medication use to treat cutaneous T cell lymphoma (CTCL).[1] It is used by mouth for advanced disease and applied to the skin for early disease.[1][3] It is used when other treatments have failed.[1][3]

Common side effects by mouth include high cholesterol, headaches, low thyroid, low white blood cells, rash, nausea, infection, dry skin, and peripheral swelling.[2] Common side effects when applied to the skin include rash and itchiness.[3] Other side effects may include liver problems, pancreatitis, and sunburns.[2] Use in pregnancy may harm the baby.[2] It is a retinoid.[1] How it works is unclear.[1]

Bexarotene was approved in the United States in 1999 and Europe in 2001.[2][1] It is available as a generic medication.[4] In the United Kingdom 100 pills of 75 mg costs the NHS about £940 as of 2021.[5] This amount in the United States is about 2,050 USD.[4]

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).[6]

It has been used off-label for non-small cell lung cancer[7] and breast cancer.[8]

Dosage

It is generally taken at a dose of 300 mg/m2/day.[1]

Contraindications

Known contraindications include:[9]

  • 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

Side 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.[6][9][10][11]

Interactions

Its plasma concentration may be increased by concomitant treatment with CYP3A4 inhibitors such as ketoconazole.[9] It may also induce CYP3A4, and hence CYP3A4 substrates like cyclophosphamide may have their plasma concentrations reduced.[9] Likewise consumption of grapefruit juice might increase bexarotene's plasma concentrations, hence potentially altering its therapeutic effects.[9]

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).[11][12][13] By so doing it induces cell differentiation and apoptosis and prevents the development of drug resistance.[14] It also has anti-angiogenic effects and inhibits cancer metastasis.[14] The retinoic acid receptors (RARs) regulate cell differentiation and proliferation whereas RXRs regulate apoptosis.[10]

Chemistry

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.[15]

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.[16]

The developer of bexarotene (brand name Targretin) was Ligand Pharmaceuticals, a San Diego biotech company which received FDA approval for the drug in 1999.[17] The FDA approved bexarotene on 29 December 1999.[18]

Japanese pharmaceutical Eisai bought the rights to Targretin and three other anti-cancer products from Ligand in 2006.[17] In the United States, patents on the drug expired in 2016.[17]

It received EMA approval on 29 March 2001.[19]

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[20][21] although subsequent studies have yielded mixed results.[22][23][24][25][26]

The results of CCMR-One, a clinical trial of the effects of bexarotene on patients with multiple sclerosis operated by the University of Cambridge,[27] 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.[28]

References

  1. 1 2 3 4 5 6 7 8 9 10 "Targretin". Archived from the original on 22 June 2021. Retrieved 10 January 2022.
  2. 1 2 3 4 5 "DailyMed - BEXAROTENE capsule". dailymed.nlm.nih.gov. Archived from the original on 1 March 2021. Retrieved 10 January 2022.
  3. 1 2 3 4 "Bexarotene (Topical) Monograph for Professionals". Drugs.com. Archived from the original on 4 March 2021. Retrieved 10 January 2022.
  4. 1 2 "Bexarotene Prices and Bexarotene Coupons - GoodRx". GoodRx. Retrieved 10 January 2022.
  5. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 982. ISBN 978-0857114105.
  6. 1 2 "TARGRETIN (BEXAROTENE) CAPSULE [CARDINAL HEALTH]". DailyMed. Cardinal Health. March 2006. Archived from the original on 12 January 2014. Retrieved 12 January 2014.
  7. ↑ Dragnev KH, Petty WJ, Shah SJ, Lewis LD, Black CC, Memoli V, et al. (March 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. doi:10.1158/1078-0432.CCR-06-1836. PMID 17363535. S2CID 25374661. Archived (PDF) from the original on 28 August 2021. Retrieved 21 June 2021.
  8. ↑ Esteva FJ, Glaspy J, Baidas S, Laufman L, Hutchins L, Dickler M, et al. (March 2003). "Multicenter phase II study of oral bexarotene for patients with metastatic breast cancer" (PDF). Journal of Clinical Oncology. 21 (6): 999–1006. doi:10.1200/JCO.2003.05.068. PMID 12637463. Archived (PDF) from the original on 6 April 2016. Retrieved 21 June 2021.
  9. 1 2 3 4 5 "Targretin Capsules - Summary of Product Characteristics". electronic Medicines Compendium. Eisai Ltd. 4 April 2013. Archived from the original on 10 May 2018. Retrieved 14 January 2014.
  10. 1 2 Brunton L, Chabner B, Knollman B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
  11. 1 2 "Targretin (bexarotene) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 18 October 2017. Retrieved 31 January 2014.
  12. ↑ Rowe A (February 1997). "Retinoid X receptors". The International Journal of Biochemistry & Cell Biology. 29 (2): 275–8. doi:10.1016/S1357-2725(96)00101-X. PMID 9147128.
  13. ↑ Dawson MI, Xia Z (January 2012). "The retinoid X receptors and their ligands". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1821 (1): 21–56. doi:10.1016/j.bbalip.2011.09.014. PMC 4097889. PMID 22020178.
  14. 1 2 Qu L, Tang X (January 2010). "Bexarotene: a promising anticancer agent". Cancer Chemotherapy and Pharmacology. 65 (2): 201–5. doi:10.1007/s00280-009-1140-4. PMID 19777233. S2CID 31266907.
  15. ↑ "Bexarotene MSDS". LC Labs. Archived from the original on 27 January 2013.
  16. ↑ "Lymphoma Treatment: Targretin (bexarotene)". Timeline of Innovation. SRI International. Archived from the original on 19 November 2016. Retrieved 20 September 2013.
  17. 1 2 3 Vinluan F (12 October 2011). "Generic cancer drug from Banner aims to take on Eisai's Targretin". MedCity News. Archived from the original on 10 May 2018. Retrieved 11 February 2012.
  18. ↑ "Bexarotene". Drugs.com. Archived from the original on 12 January 2014. Retrieved 12 January 2014.
  19. ↑ "Targretin : EPAR - Product Information" (PDF). European Medicines Agency. Eisai Ltd. 3 April 2013. Archived (PDF) from the original on 10 May 2018. Retrieved 12 January 2014.
  20. ↑ Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, et al. (March 2012). "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 335 (6075): 1503–6. Bibcode:2012Sci...335.1503C. doi:10.1126/science.1217697. PMC 3651582. PMID 22323736.
  21. ↑ MedicalXpress (9 February 2012). "FDA-approved drug rapidly clears amyloid from the brain, reverses Alzheimer's symptoms in mice". MedicalXpress. Archived from the original on 10 February 2012. Retrieved 14 February 2012.
  22. ↑ Fitz NF, Cronican AA, Lefterov I, Koldamova R (May 2013). "Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models"". Science. 340 (6135): 924–c. Bibcode:2013Sci...340..924F. doi:10.1126/science.1235809. PMC 4086452. PMID 23704552.
  23. ↑ Price AR, Xu G, Siemienski ZB, Smithson LA, Borchelt DR, Golde TE, Felsenstein KM (May 2013). "Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models"". Science. 340 (6135): 924–d. Bibcode:2013Sci...340..924P. doi:10.1126/science.1234089. PMID 23704553.
  24. ↑ Tesseur I, Lo AC, Roberfroid A, Dietvorst S, Van Broeck B, Borgers M, et al. (May 2013). "Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models"". Science. 340 (6135): 924–e. Bibcode:2013Sci...340R.924T. doi:10.1126/science.1233937. PMID 23704554.
  25. ↑ Veeraraghavalu K, Zhang C, Miller S, Hefendehl JK, Rajapaksha TW, Ulrich J, et al. (May 2013). "Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models"". Science. 340 (6135): 924–f. Bibcode:2013Sci...340..924V. doi:10.1126/science.1235505. PMID 23704555.
  26. ↑ "Anti-Cancer Drug Reverses Alzheimer's Disease In Mice". Medical News Today. 25 May 2013. Archived from the original on 10 May 2018. Retrieved 21 June 2021.
  27. ↑ "Trials in Cambridge". Cambridge Neuroimmunology. Archived from the original on 13 March 2021. Retrieved 25 September 2020.
  28. ↑ "MS treatment a step closer after drug shown to repair nerve coating". the Guardian. 25 September 2020. Archived from the original on 4 May 2021. Retrieved 25 September 2020.
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