Napabucasin Drug‐Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers
| العنوان: | Napabucasin Drug‐Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers |
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| المؤلفون: | Matthew Hitron, Michael D. Karol, Marjie L. Hard, Xiaoshu Dai, Colleen F. Mclaughlin, Scott J. Brantley, Matthew T. Goulet |
| المصدر: | Clinical Pharmacology in Drug Development |
| بيانات النشر: | John Wiley and Sons Inc., 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 2160-7648 2160-763X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dd249a6a220f2dc5c28a0e4212bd82e9Test http://europepmc.org/articles/PMC8453567Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....dd249a6a220f2dc5c28a0e4212bd82e9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21607648 2160763X |
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