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Pharmacology and pharmacokinetics of tazemetostat

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Abstract

Tazemetostat, a novel oral selective inhibitor of enhancer of zeste homolog 2 (EZH2), was approved by the Food and Drug Administration (FDA) in 2020 for use in patients with advanced epithelioid sarcoma or relapsed/refractory (R/R) EZH2-mutated follicular lymphoma. These indications were approved by the FDA trough accelerated approval based on objective response rate and duration of response that resulted from phase 2 clinical trials. Tazemetostat competes with S-adenosylmethionine (SAM) cofactor to inhibit EZH2, reducing the levels of trimethylated lysine 27 of histone 3 (H3K27me3), considered as pharmacodynamic marker. Tazemetostat is orally bioavailable, characterized by rapid absorption and dose-proportional exposure, which is not influenced by coadministration with food or gastric acid reducing agents. It highly distributes in tissues, but with limited access to central nervous system. Tazemetostat is metabolized by CYP3A in the liver to 3 major inactive metabolites (M1, M3, and M5), has a short half-life and is mainly excreted in feces. Drug-drug interactions were shown with moderate CYP3A inhibitors as fluconazole, leading the FDA to recommend a 50% dose reduction, while studies investigating coadministration of tazemetostat with strong inhibitors/inducers are ongoing. No dosage modifications are recommended based on renal or hepatic dysfunctions. Overall, tazemetostat is the first-in-class EZH2 inhibitor approved by the FDA for cancer treatment. Current clinical studies are evaluating combination therapies in patients with several malignancies.

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Funding

Support: Grant UM1CA186690 (NCI-CTEP), U24CA247643 (NCI), and P30CA47904 (NCI).

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Authors and Affiliations

  1. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Room G27E, Hillman Research Pavilion, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA

    Marco Orleni & Jan H. Beumer

  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Marco Orleni & Jan H. Beumer

  3. Doctoral School in Pharmacological Sciences, University of Padua, Padua, Italy

    Marco Orleni

  4. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Jan H. Beumer

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  1. Marco Orleni
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M.O. and J.H.B. wrote the main manuscript text and prepared figure and table. All authors reviewed the manuscript.

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Correspondence to Jan H. Beumer.

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Orleni, M., Beumer, J.H. Pharmacology and pharmacokinetics of tazemetostat. Cancer Chemother Pharmacol 93, 509–517 (2024). https://doi.org/10.1007/s00280-024-04658-4

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  • DOI: https://doi.org/10.1007/s00280-024-04658-4

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