Tazemetostat

Uses

Tazemetostat is a methyltransferase inhibitor indicated to treat patients 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.

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.

Tazemetostat is also used to associated treatment for these conditions: Locally Advanced Epithelioid Sarcoma, Metastatic Epithelioid Sarcoma

How Tazemetostat works

EZH2 is a methyltransferase subunit of the polycomb repressive complex 2 (PRC2) which catalyzes multiple methylations of lysine 27 on histone H3 (H3K27). Trimethylation of this lysine inhibits the transcription of genes associated with cell cycle arrest. PRC2 is antagonized by the switch/sucrose non-fermentable (SWI/SNF) multiprotein complex. Abnormal activation of EZH2 or loss of function mutations in SWI/SNF lead to hyper-trimethylation of H3K27. Hyper-trimethylation of H3K27 leads to cancer cell de-differentiation, a gain of cancer stem cell-like properties. De-differentiation can allow for cancer cell proliferation.

Tazemetostat inhibits EZH2, preventing hyper-trimethylation of H3K27 and an uncontrollable cell cycle.

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.

Food Interaction

• Take with or without food.

[Major] GENERALLY AVOID: Consumption of grapefruit or grapefruit juice during tazemetostat therapy may significantly increase the plasma concentrations of tazemetostat.

The proposed mechanism is inhibition of the CYP450 3A4-mediated metabolism of tazemetostat by certain compounds in grapefruit.

Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability).

According to the product labeling, coadministration of tazemetostat (400 mg twice daily) with the moderate CYP450 3A4 inhibitor fluconazole increased the tazemetostat steady state exposure (AUC 0 to 8 hours) by 3.1-fold and peak plasma concentration by 2.3-fold.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

Clinically, this interaction may result in an increased risk of the frequency or severity of adverse reactions due to tazemetostat such as hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress.

MANAGEMENT: The manufacturer advises that patients treated with tazemetostat should avoid consumption of grapefruit or grapefruit juice.

Tazemetostat Disease Interaction

Moderate: hepatic impairment

Volume of Distribution

Tazemetostat has a volume of distribution of 1230L.

Elimination Route

Tazemetostat 800mg twice daily leads to a C_max of 829ng/mL, with a T_max 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.

Half Life

Tazemetostat has a terminal elimination half life of 3.1h.

Clearance

Tazemetostat has an apparent total clearance of 274L/h.

Elimination Route

Tazemetostat is 15% eliminated in urine and 79% eliminated in feces.

Innovators Monograph

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