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

British journal of clinical pharmacology 2019 Jul

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

Citation

Hélène Faessel, John Nemunaitis, Todd M Bauer, A Craig Lockhart, Douglas V Faller, Farhad Sedarati, Xiaofei Zhou, Karthik Venkatakrishnan, R Donald Harvey. Effect of CYP3A inhibitors on the pharmacokinetics of pevonedistat in patients with advanced solid tumours. British journal of clinical pharmacology. 2019 Jul;85(7):1464-1473