Napabucasin Drug‐Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers

Autor: Matthew Hitron, Michael D. Karol, Marjie L. Hard, Xiaoshu Dai, Colleen F. Mclaughlin, Scott J. Brantley, Matthew T. Goulet
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Male
Organic anion transporter 1
Flurbiprofen
Pharmaceutical Science
Administration
Oral
Pharmacology
030226 pharmacology & pharmacy
Dextromethorphan
0302 clinical medicine
phase 1 trial
Cytochrome P-450 Enzyme System
ATP Binding Cassette Transporter
Subfamily G
Member 2
Pharmacology (medical)
Drug Interactions
Rosuvastatin Calcium
Omeprazole
biology
Hydroxybupropion
Articles
Repaglinide
Healthy Volunteers
Neoplasm Proteins
030220 oncology & carcinogenesis
Female
breast cancer resistance protein transporter
medicine.drug
Half-Life
Adult
drug‐drug interactions
cytochrome P450
Midazolam
napabucasin
Original Manuscript
03 medical and health sciences
Young Adult
Pharmacokinetics
Caffeine
medicine
Humans
Bupropion
Benzofurans
business.industry
Gene Expression Regulation
biology.protein
business
Naphthoquinones
Zdroj: Clinical Pharmacology in Drug Development
ISSN: 2160-7648
2160-763X
Popis: Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug‐drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1‐11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug‐drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration–time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%‐141.4%]), intravenous midazolam (118% [94.4%‐147.3%]), repaglinide (127% [104.7%‐153.3%]), and rosuvastatin (213% [42.5%‐1068.3%]) and decreased the area under the plasma concentration–time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%‐108.3%]), bupropion (79% [64.6%‐97.0%]), and hydroxybupropion (45% [15.7%‐129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.
Databáze: OpenAIRE
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