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Endoxifen
Clinical data
Trade names	Zonalta
Other names	4-Hydroxy-N-desmethyltamoxifen; Desmethylhydroxytamoxifen
Routes of; administration	By mouth
Identifiers
	IUPAC name 4-[1-[4-[2-(methylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol;
CAS Number	112093-28-4 ; 114828-90-9 (E-isomer); 1032008-74-4 (hydrochloride);
PubChem CID	130621;
UNII	46AF8680RC;
ChEMBL	ChEMBL1949791;
PDB ligand	9XY (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID80149880 ;
ECHA InfoCard	100.208.548
Chemical and physical data
Formula	C25H27NO2
Molar mass	373.496 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CCC(=C(C1=CC=C(C=C1)O)C2=CC=C(C=C2)OCCNC)C3=CC=CC=C3;
	InChI 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]