Back to Search
Start Over
Effect of CYP3A inhibitors on the pharmacokinetics of pevonedistat in patients with advanced solid tumours.
- Source :
- British Journal of Clinical Pharmacology; Jul2019, Vol. 85 Issue 7, p1464-1473, 10p, 3 Charts, 2 Graphs
- Publication Year :
- 2019
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- PHARMACOKINETICS
P-glycoprotein
ITRACONAZOLE
CYTOCHROME P-450
TUMORS
FLUCONAZOLE
Subjects
Details
- Language :
- English
- ISSN :
- 03065251
- Volume :
- 85
- Issue :
- 7
- Database :
- Complementary Index
- Journal :
- British Journal of Clinical Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 137200431
- Full Text :
- https://doi.org/10.1111/bcp.13915