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

Hélène Faessel, John Nemunaitis, Todd M. Bauer, A. Craig Lockhart, Douglas V. Faller, Farhad Sedarati, Xiaofei Zhou, Karthik Venkatakrishnan, R. Donald Harvey

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1464-1473
Number of pages10
JournalBritish Journal of Clinical Pharmacology
Volume85
Issue number7
DOIs
StatePublished - Jul 2019

Keywords

  • anticancer drugs
  • drug interactions
  • patient safety
  • pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Faessel, H., Nemunaitis, J., Bauer, T. M., Lockhart, A. C., Faller, D. V., Sedarati, F., Zhou, X., Venkatakrishnan, K., & Harvey, R. D. (2019). Effect of CYP3A inhibitors on the pharmacokinetics of pevonedistat in patients with advanced solid tumours. British Journal of Clinical Pharmacology, 85(7), 1464-1473. https://doi.org/10.1111/bcp.13915