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Author Notes:

Hélène Faessel, PharmD, PhD, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA 02139, USA. Email:Helene.Faessel@Takeda.com

The authors confirm that the PI for this paper is Dr R. Donald Harvey and that he had direct clinical responsibility for patients.

CONTRIBUTORS: All authors contributed to the writing and critically revised the manuscript, reviewed and approved the final version of the manuscript, and agreed to be accountable for all aspects of the work.

COMPETING INTERESTS: H.F., D.V.F., F.S., X.Z. and K.V. are employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

H.F. owns stock with Takeda Pharmaceutical International Co. J.N. is an employee, serves in a leadership role, and has patents, royalties and other intellectual property at Gradalis, Inc.; had a consultancy or advisory role and served on the speakers' bureau for Amgen and AstraZeneca; received honoraria from Amgen and AstraZeneca; and received travel accommodation/expenses from Takeda Pharmaceutical Company Limited, Amgen, Baxalta and AstraZeneca.

T.M.B. had a consultancy or advisory role for Guardant Health, Ignyta, Loxo, Moderna Therapeutics and Pfizer; and received research support from Abbvie, Aileron Therapeutics, Amgen, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol‐Myers Squibb, Calithera Biosciences, Daiichi Sankyo, Deciphera, Five Prime Therapeutics, Genentech/Roche, GlaxoSmithKline, Ignyta, Immunocore, Immunogen, Incyte, Jacobio, Kolltan Pharmaceuticals, Leap Therapeutics, Lilly, MabVax, MedImmune, Medpacto, Inc., Merck, Merrimack, Millennium Pharmaceuticals, Inc., Mirati Therapeutics, Moderna Therapeutics, Novartis, Peleton, Pfizer, Principa Biopharma, Roche, Sanofi and Stemline Therapeutics.

A.C.L. has nothing to disclose. R.D.H. received research support from Takeda Pharmaceutical Company Limited, outside the submitted work.

Subjects:

Research Funding:

This work was supported by funding from Millennium Pharmaceuticals, Inc. The authors acknowledge Ying Jean, PhD, of FireKite (an Ashfield Company, part of UDG Healthcare plc), for medical writing support of this manuscript, which was funded by Millennium Pharmaceuticals, Inc., in compliance with Good Publication Practice 3 ethical guidelines (Battisti et al., Ann Intern Med 2015;163:461–464), and Janice Y. Ahn, PhD (Millennium Pharmaceuticals, Inc.), for editorial support.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Pharmacology & Pharmacy
  • anticancer drugs
  • drug interactions
  • patient safety
  • pharmacokinetics
  • NEDD8-ACTIVATING ENZYME-INHIBITOR
  • ACUTE MYELOID-LEUKEMIA
  • CONCISE GUIDE
  • PHASE-I
  • MLN4924
  • TAK-924/MLN4924
  • FLUCONAZOLE
  • PROTEASOME
  • LIGASES

Effect of CYP3A inhibitors on the pharmacokinetics of pevonedistat in patients with advanced solid tumours

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Journal Title:

British Journal of Clinical Pharmacology

Volume:

Volume 85, Number 7

Publisher:

, Pages 1464-1473

Type of Work:

Article | Final Publisher PDF

Abstract:

Aims: This phase I study evaluated the effects of the moderate cytochrome P450 (CYP) 3A inhibitor fluconazole and the strong CYP3A/P-glycoprotein (P-gp) inhibitor itraconazole on the pharmacokinetics of the investigational neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme inhibitor pevonedistat in patients with advanced solid tumours. Methods: Patients received single doses of intravenous pevonedistat 8 mg m−2, alone and with fluconazole (loading: 400 mg; maintenance: 200 mg once daily), or pevonedistat 8, 15 or 20 mg m−2, alone and with itraconazole 200 mg once daily. Serial blood samples for pevonedistat pharmacokinetics were obtained pre- and post-infusion on days 1 (alone) and 8 (with fluconazole/itraconazole). After completing the pharmacokinetic portion, patients remaining on study received pevonedistat with docetaxel or carboplatin and paclitaxel. Results: The ratios of geometric mean area under the concentration–time curves (n; 90% confidence interval) of pevonedistat in the presence vs. absence of fluconazole or itraconazole were 1.11 (12; 1.03–1.19) and 1.14 (33; 1.07–1.23), respectively. Fifty patients (98%) experienced at least one adverse event (AE), with maximum severity of grade 1–2 in 28 patients (55%) and of grade ≥3 in 22 patients (43%). The most common drug-related AEs were vomiting (12%), diarrhoea (10%) and nausea (8%). No new safety findings were observed for pevonedistat. Conclusions: Fluconazole or itraconazole had insignificant effects on pevonedistat pharmacokinetics, indicating minor contributions of CYP3A/P-gp to pevonedistat clearance. The safety profile of single doses of pevonedistat plus steady-state fluconazole or itraconazole was consistent with prior clinical experience, with no new safety signals observed.

Copyright information:

© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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

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