Endoxifen
Clinical data
Trade namesZonalta
Other names4-Hydroxy-N-desmethyltamoxifen; Desmethylhydroxytamoxifen
Routes of
administration		By mouth
Identifiers
  • 4-[1-[4-[2-(methylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol
CAS Number
PubChem CID
UNII
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.208.548
Chemical and physical data
FormulaC25H27NO2
Molar mass373.496 g·mol−1
3D model (JSmol)
  • CCC(=C(C1=CC=C(C=C1)O)C2=CC=C(C=C2)OCCNC)C3=CC=CC=C3
  • InChI=1S/C25H27NO2/c1-3-24(19-7-5-4-6-8-19)25(20-9-13-22(27)14-10-20)21-11-15-23(16-12-21)28-18-17-26-2/h4-16,26-27H,3,17-18H2,1-2H3
  • Key:MHJBZVSGOZTKRH-UHFFFAOYSA-N

Endoxifen, also known as 4-hydroxy-N-desmethyltamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group as well as a protein kinase C (PKC) inhibitor. It is under development for the treatment of estrogen receptor-positive breast cancer and for the treatment of mania in bipolar disorder.[1][2] It is taken by mouth.[2]

Endoxifen is an active metabolite of tamoxifen and has been found to be effective in patients that have failed previous hormonal therapies (tamoxifen, aromatase inhibitors, and fulvestrant). [3][4][5] The prodrug tamoxifen is metabolized by the CYP2D6 enzyme to produce endoxifen and afimoxifene (4-hydroxytamoxifen).[6]

Currently, endoxifen is approved by Drugs Controller General of India for the acute treatment of manic episode with or without mixed features of Bipolar I disorder.[7] It is manufactured and sold by Intas Pharmaceuticals under the brand name Zonalta.[8]

Medical uses

Bipolar disorder

Endoxifen is used to treat manic or mixed episodes associated with bipolar I disorder in India.[9][7] It has been found that the endoxifen improves manic symptoms as well as mixed episode symptoms of patients with bipolar I disorder and has been considered an effective and well-tolerated treatment for this condition.[10]

Bipolar disorder is associated with overactive protein kinase C (PKC) intracellular signaling.[11] To date, there have been three phases of clinical trials. And, in the phase III trials, endoxifen reduced the total Young Mania Rating Scale (YMRS) score from 33.1 to 17.8. A significant (p < 0.001) improvement in Montgomery–Åsberg Depression Rating Scale (MADRS) score was observed for endoxifen (4.8 to 2.5). The endoxifen is well-tolerated by the subjects as depicted in the changes in Clinical Global Impression-Severity of Illness scores.[12]

Side effects

The most prevalent side effects for endoxifen include headache, vomiting, insomnia. Other side effects were: gastritis, epigastric discomfort, diarrhea, restlessness, somnolence, etc.[8] Some of the adverse events reported with other therapies for the management of manic episodes of bipolar I disorder were not observed during the clinical development program of endoxifen like reduction in platelet count, change in blood thyroid-stimulating hormone levels. There were no deaths, serious or significant adverse events during the conduct of trials. Overall, endoxifen was found to be well-tolerated and safe in patients of bipolar I disorder with acute manic episodes with or without mixed features.[12][10] An important caveat here is that the trial was of very short duration (only three weeks). The long-term safety of Endoxifen has not been established among patients with Bipolar Disorder.

Pharmacology

Pharmacodynamics

Selective estrogen receptor modulator

Endoxifen is a selective estrogen receptor modulator (SERM) with estrogenic and antiestrogenic actions. In the first study to evaluate the pharmacology of endoxifen, it showed 25% of the affinity of estradiol for the estrogen receptor (ER) while afimoxifene had 35% of the affinity of estradiol for the ER.[13] The antiestrogenic actions of endoxifen and afimoxifene in this study were very similar.[13] In another study, the affinity of endoxifen for the ERα was 12.1% and its affinity for the ERβ was 4.75% relative to estradiol.[14] For comparison, afimoxifene had relative binding affinities for the ERα and ERβ of 19.0% and 21.5% compared to estradiol, respectively.[14] In yet another investigation, both endoxifen and afimoxifene had 181% of the affinity of estradiol for the ER whereas tamoxifen had 2.8% and N-desmethyltamoxifen had 2.4%.[15]

Protein kinase C inhibition

The exact mechanism by which endoxifen exerts its therapeutic effects has not been established in bipolar I disorder. However, the efficacy of endoxifen could be mediated through protein kinase C (PKC). The PKC represents a family of enzymes highly enriched in the brain, where it plays a major role in regulating both pre-and post-synaptic aspects of neurotransmission. Excessive activation of PKC results in symptoms related to bipolar disorder. The PKC signaling pathway is a target for the actions of two structurally dissimilar antimanic agents – lithium and valproate.[8]

Endoxifen exhibits 4-fold higher potency in inhibiting PKC activity compared to tamoxifen in preclinical studies and is not dependent on the isozyme cytochrome P450 2D6 (CYP2D6) for action on the target tissues.[16]

Pharmacokinetics

Orally administered endoxifen is rapidly absorbed and systemically available. The time to peak (Tmax) is between 4.5 and 6 hours after oral administration. It is not metabolized by cytochrome P450 enzymes. The half-life (t½) life of endoxifen is 52.1 to 58.1 hours.[17]

Research

Endoxifen has been investigated as a potential drug in the treatment of breast cancer.[18][19]

References

  1. ↑ "Z-endoxifen hydrochloride". NCI Drug Dictionary.
  2. 1 2 "Endoxifen - Intas Pharmaceuticals/Jina pharmaceuticals - AdisInsight".
  3. ↑ Hawse JR, Subramaniam M, Cicek M, Wu X, Gingery A, Grygo SB, et al. (2013). "Endoxifen's molecular mechanisms of action are concentration dependent and different than that of other anti-estrogens". PLOS ONE. 8 (1): e54613. Bibcode:2013PLoSO...854613H. doi:10.1371/journal.pone.0054613. PMC 3557294. PMID 23382923.
  4. ↑ Wu X, Hawse JR, Subramaniam M, Goetz MP, Ingle JN, Spelsberg TC (March 2009). "The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells". Cancer Research. 69 (5): 1722–7. doi:10.1158/0008-5472.CAN-08-3933. PMID 19244106.
  5. ↑ Gingery A, Subramaniam M, Pitel KS, Reese JM, Cicek M, Lindenmaier LB, et al. (2014). "The effects of a novel hormonal breast cancer therapy, endoxifen, on the mouse skeleton". PLOS ONE. 9 (5): e98219. Bibcode:2014PLoSO...998219G. doi:10.1371/journal.pone.0098219. PMC 4031133. PMID 24853369.
  6. ↑ Wilcken N (2016). "Breast cancer: a disease of subtypes". Cancer Forum. 40 (3).
  7. 1 2 "List of new drugs approved in the year 2019 till date" (PDF). Central Drugs Standard Control Organisation. 1 October 2021. p. 4.
  8. 1 2 3 "Drug Fact Sheet - Zonalta" (PDF). Intas Pharmaceuticals. 1 October 2021.
  9. ↑ Rankovic Z, Bingham M, Hargreaves R (2012-11-02). Drug Discovery for Psychiatric Disorders. Drug Discovery. Royal Society of Chemistry. doi:10.1039/9781849734943. ISBN 978-1-84973-365-6.
  10. 1 2 Ahmad A, Sheikh S, Shah T, Reddy MS, Prasad B, Verma KK, et al. (October 2016). "Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen". Clinical and Translational Science. 9 (5): 252–259. doi:10.1111/cts.12407. PMC 5350997. PMID 27346789.
  11. ↑ Zarate CA, Manji HK (2009). "Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder". CNS Drugs. 23 (7): 569–82. doi:10.2165/00023210-200923070-00003. PMC 2802274. PMID 19552485.
  12. 1 2 Ahmad A, Sheikh S, Khan MA, Chaturvedi A, Patel P, Patel R, et al. (December 2020). "Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder". Bipolar Disorders. 23 (6): 595–603. doi:10.1111/bdi.13041. PMID 33368969. S2CID 229688331.
  13. 1 2 Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, et al. (May 2004). "Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen". Breast Cancer Research and Treatment. 85 (2): 151–9. doi:10.1023/B:BREA.0000025406.31193.e8. hdl:2027.42/44223. PMID 15111773. S2CID 37932.
  14. 1 2 Kelly PM, Keely NO, Bright SA, Yassin B, Ana G, Fayne D, et al. (August 2017). "Novel Selective Estrogen Receptor Ligand Conjugates Incorporating Endoxifen-Combretastatin and Cyclofenil-Combretastatin Hybrid Scaffolds: Synthesis and Biochemical Evaluation". Molecules. 22 (9): 1440. doi:10.3390/molecules22091440. PMC 6151695. PMID 28858267.
  15. ↑ Maximov PY, McDaniel RE, Fernandes DJ, Bhatta P, Korostyshevskiy VR, Curpan RF, Jordan VC (October 2014). "Pharmacological relevance of endoxifen in a laboratory simulation of breast cancer in postmenopausal patients". Journal of the National Cancer Institute. 106 (10). doi:10.1093/jnci/dju283. PMC 4271116. PMID 25258390.
  16. ↑ Ali SM, Ahmad A, Shahabuddin S, Ahmad MU, Sheikh S, Ahmad I (April 2010). "Endoxifen is a new potent inhibitor of PKC: a potential therapeutic agent for bipolar disorder". Bioorganic & Medicinal Chemistry Letters. 20 (8): 2665–7. doi:10.1016/j.bmcl.2010.02.024. PMID 20227879.
  17. ↑ Ahmad A, Shahabuddin S, Sheikh S, Kale P, Krishnappa M, Rane RC, Ahmad I (December 2010). "Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects". Clinical Pharmacology & Therapeutics. 88 (6): 814–7. doi:10.1038/clpt.2010.196. PMID 20981001. S2CID 24590365.
  18. ↑ Issues in Pharmacology, Pharmacy, Drug Research, and Drug Innovation: 2011 Edition. ScholarlyEditions. 2012-01-09. ISBN 978-1-4649-6344-5.
  19. ↑ Goetz MP (February 2018). "The development of endoxifen for breast cancer". Clinical Advances in Hematology & Oncology. 16 (2): 102–105. PMC 7864591. PMID 29741509.
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