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Effect of CYP3A inhibitors on the pharmacokinetics of pevonedistat in patients with advanced solid tumours
Author(s) -
Faessel Hélène,
Nemunaitis John,
Bauer Todd M.,
Lockhart A. Craig,
Faller Douglas V.,
Sedarati Farhad,
Zhou Xiaofei,
Venkatakrishnan Karthik,
Harvey R. Donald
Publication year - 2019
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13915
Subject(s) - pharmacokinetics , fluconazole , itraconazole , carboplatin , pharmacology , medicine , nausea , adverse effect , docetaxel , gastroenterology , chemotherapy , cisplatin , antifungal , dermatology
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.