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Author Notes:

Neeraj Gupta, Phone: +1 617 444 2119, Email:neeraj.gupta@takeda.com

ll editorial procedures complied with Good Publication Practice-3 (GPP3) guidelines (Battisti WP, et al. Ann Intern Med. 2015;163(6):461–464).

Conflicts of interest: Neeraj Gupta, Michael J. Hanley, Cindy Xia, Richard Labotka, and Karthik Venkatakrishnan are employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. R. Donald Harvey discloses research funding to his institution from Takeda.

Subjects:

Research Funding:

Writing assistance was funded by Millennium Pharmaceuticals, Inc.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Pharmacology & Pharmacy
  • PLUS LENALIDOMIDE-DEXAMETHASONE
  • TWICE-WEEKLY IXAZOMIB
  • ADVANCED SOLID TUMORS
  • MULTIPLE-MYELOMA
  • PERIPHERAL NEUROPATHY
  • CONTINUOUS THERAPY
  • RENAL IMPAIRMENT
  • DRUG DISPOSITION
  • FIXED DURATION
  • PHARMACOKINETICS

Clinical Pharmacology of Ixazomib: The First Oral Proteasome Inhibitor

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Journal Title:

Clinical Pharmacokinetics

Volume:

Volume 58, Number 4

Publisher:

, Pages 431-449

Type of Work:

Article | Final Publisher PDF

Abstract:

Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Ixazomib is a selective, potent, and reversible inhibitor of the 20S proteasome, and preferentially binds to and inhibits the β5 chymotrypsin-like proteolytic site. Ixazomib absorption is rapid, with a median time to reach maximum plasma concentration of approximately 1 h post-dose. Ixazomib pharmacokinetics (PK) are adequately described by a three-compartment model (terminal half-life of 9.5 days) with first-order linear absorption (oral bioavailability of 58%). Plasma exposures of ixazomib increase in a dose-proportional manner. A high-fat meal decreases both the rate and extent of ixazomib absorption, supporting administration on an empty stomach. Population PK analyses demonstrated that no dose adjustment is required based on age, body size/weight, race, sex, mild-to-moderate renal impairment, or mild hepatic impairment. Results from dedicated studies indicate that a reduced starting dose (from 4 to 3 mg) is appropriate for patients with severe renal impairment, end-stage renal disease requiring dialysis, or moderate-to-severe hepatic impairment. Non-cytochrome P450 (CYP)-mediated metabolism appears to be the major clearance mechanism for ixazomib. Drug–drug interaction studies have shown no meaningful effects of strong inhibitors of CYP3A on ixazomib PK; however, the strong inducer rifampin caused a clinically relevant reduction in ixazomib exposure, supporting the recommendation to avoid concomitant administration of ixazomib with strong CYP3A inducers. Exposure–response analyses of data from the phase III TOURMALINE-MM1 registrational study demonstrate a favorable benefit–risk profile for the approved dose and regimen of weekly ixazomib 4 mg on days 1, 8, and 15 of each 28-day cycle.

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© 2018, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/).

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