Currently, endoxifen is approved byDrugs 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 byIntas Pharmaceuticals under the brand nameZonalta.[8]
Endoxifen is used to treatmanic ormixed episodes associated withbipolar I disorder inIndia.[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 overactiveprotein 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 totalYoung Mania Rating Scale (YMRS) score from 33.1 to 17.8. A significant (p < 0.001) improvement inMontgomery–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 inClinical Global Impression-Severity of Illness scores.[12]
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.[citation needed]
Endoxifen is aselective estrogen receptor modulator (SERM) withestrogenic andantiestrogenic actions. In the first study to evaluate the pharmacology of endoxifen, it showed 25% of theaffinity ofestradiol for theestrogen receptor (ER) whileafimoxifene 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 theERα was 12.1% and its affinity for theERβ was 4.75% relative toestradiol.[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 andafimoxifene had 181% of the affinity of estradiol for the ER whereas tamoxifen had 2.8% andN-desmethyltamoxifen had 2.4%.[15]
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 throughprotein 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 andvalproate.[8]
Endoxifen exhibits 4-fold higher potency in inhibiting PKC activity compared totamoxifen in preclinical studies and is not dependent on the isozyme cytochrome P450 2D6 (CYP2D6) for action on the target tissues.[16]
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 bycytochrome P450 enzymes. The half-life (t½) life of endoxifen is 52.1 to 58.1 hours.[17]
^abAhmad 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.PMID33368969.S2CID229688331.
^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.PMID20981001.S2CID24590365.
