Effect of CYP3A inhibitors on the pharmacokinetics of pevonedistat in patients with advanced solid tumours.
Br J Clin Pharmacol
; 85(7): 1464-1473, 2019 07.
Article
em En
| MEDLINE
| ID: mdl-30845347
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
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Protocolos de Quimioterapia Combinada Antineoplásica
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Ciclopentanos
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Inibidores do Citocromo P-450 CYP3A
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Neoplasias
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Br J Clin Pharmacol
Ano de publicação:
2019
Tipo de documento:
Article