Tazemetostat (EPZ-6438)

Absorption

Tazemetostat 800mg twice daily leads to a Cmax of 829ng/mL, with a Tmax of 1-2 hours , and an AUC of 3340ng*h/mL. Absorption is not significantly affected by a high fat, high calorie meal. Tazemetostat is 33% bioavailable.

Toxicity

Data regarding the presentation and management of tazemetostat overdoses are not readily available. The most common adverse reactions associated with tazemetostat are pain, fatigue, nausea, decreased appetite, vomiting, and constipation.

Description

Tazemetostat (1403254-99-8) is a potent (Ki = 2.5nM wild type human PRC2-containing) and selective SAM-competitive inhibitor of the lysine methyltransferase EZH2.1?Tazemetostat displayed strong antiproliferative effects against SMARCB1-deleted malignant rhabdoid tumor (MRT) cell lines?in vitro. This antitumor activity was also observed in SMARTCB1 mutant mouse xenografts. It displayed potent antitumor activity in various cancer models including non-Hodgkins lymphoma2, pediatric glioma3, small-cell carcinoma of the ovary4, and synovial sarcomas5. Tazemetostat has also been shown to control inflammatory genes by modulating IRF1, IRF8, and STAT1 levels suggesting therapeutic potential for the treatment of neuroinflammatory diseases associated with microglial activation.6

The Uses of Tazemetostat (EPZ-6438)

EPZ 6438 is a potent and selective inhibitor of EZH2.

Indications

Tazemetostat is indicated to treat adult and pediatric patients 16 years and older with metastatic or locally advanced epithelioid sarcoma that is not eligible for complete resection. It is also indicated to treat adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an IZH2 mutation and who have received at least 2 prior systemic therapies. Additionally, it is indicated in adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options.

Background

Tazemetostat is a methyltransferase inhibitor used to treat metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. Tazemetostat was first named in literature as EPZ-6438.
Tazemetaostat was granted FDA approval on 23 January 2020.

Biological Activity

Tazemetostat (EPZ-6438) is a potent, and selective EZH2 inhibitor with K i and IC50 of 2.5 nM and 11 nM in cell-free assays, exhibiting a 35-fold selectivity versus EZH1 and >4,500-fold selectivity relative to 14 other HMT.

Pharmacokinetics

Tazemetostat is a methyltransferase inhibitor that prevents hyper-trimethylation of histones and inhibits cancer cell de-differentiation. The duration of action is long as it is given twice daily. Patients should be counselled regarding the risk of secondary malignancies and embryo-fetal toxicity.

Metabolism

Tazemetostat is metabolized by CYP3A4 to an inactive desethyl metabolite and one other inactive metabolite not described.

References

1) Knutson?et al.?(2013),?Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2;?Proc. Natl. Acad. Sci. USA?110?7922 2) Knutson?et al.?(2014),?Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma; Mol.Cancer Ther.?13?842 3) Mohammad?et al. (2017),?EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas; Nat. Med.?23?483 4) Chan-Penebre?et al.?(2017),?Selective killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models; Mol. Cancer Ther.?16?850 5) Kawano?et al.?(2016),?Preclinical Evidence of Anti-Tumor Activity by EZH2 Inhibition in Human Models of Synovial Sarcoma; PLoS One?11?e0158888 6) Arifuzzaman?et al.?(2017),?Selective inhibition of EZH2 by a small molecule inhibitor regulates microglial gene expression essential for inflammation; Biochem. Pharmacol.?137?61