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

• Type of Material: Article
• Authors: Hélène Faessel, Millennium Pharmaceuticals, Inc.; John Nemunaitis, University of Toledo; Todd M. Bauer, Tennessee Oncology, PLLC; A. Craig Lockhart, University of Miami; Douglas V. Faller, Millennium Pharmaceuticals, Inc.; Farhad Sedarati, Millennium Pharmaceuticals, Inc.; Xiaofei Zhou, Millennium Pharmaceuticals, Inc.; Karthik Venkatakrishnan, Millennium Pharmaceuticals, Inc.; R Donald Harvey, Emory University
• Language: English
• Date: 2019-07-01
• Publisher: Wiley: 12 months
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1111/bcp.13915
• Title of Journal or Parent Work: British Journal of Clinical Pharmacology
• ISSN: 0306-5251
• Volume: 85
• Issue: 7
• Start Page: 1464
• End Page: 1473
• Grant/Funding Information: 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; TAK-924/MLN4924; LIGASES; anticancer drugs; Pharmacology & Pharmacy; NEDD8-ACTIVATING ENZYME-INHIBITOR; PHASE-I; Life Sciences & Biomedicine; CONCISE GUIDE; PROTEASOME; pharmacokinetics; MLN4924; ACUTE MYELOID-LEUKEMIA; FLUCONAZOLE; drug interactions; patient safety
• Research Categories: Chemistry, Pharmaceutical; Health Sciences, Pharmacology

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.