Effects of a reactive oxygen species generator, napabucasin (BBI608), on tolerability, safety, pharmacokinetics, and QT/QTc interval in healthy volunteers

Abstract This study examined the safety, tolerability, and pharmacokinetics (PK) of napabucasin in healthy Asian and non‐Asian participants and investigated the potential for QT/QTc interval prolongation. This five‐part (A–E) study proceeded in a stepwise manner, unless stopping criteria were met. P...

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Auteurs principaux:	Naoto Noda, Takeshi Takagaki, Yasuhide Yodo, Yuzo Horibuchi, Shuichi Iino, Shunji Matsuki, Yoichiro Ogama, Hiroyoshi Kakuyama
Format:	article
Langue:	EN
Publié:	Wiley 2021
Sujets:	Asian healthy volunteers napabucasin non‐Asian pharmacokinetics QT/QTc interval Therapeutics. Pharmacology RM1-950
Accès en ligne:	https://doaj.org/article/b804592a5ce74d749d7cb7315b7cacf7
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spelling	oai:doaj.org-article:b804592a5ce74d749d7cb7315b7cacf72021-11-16T13:45:55ZEffects of a reactive oxygen species generator, napabucasin (BBI608), on tolerability, safety, pharmacokinetics, and QT/QTc interval in healthy volunteers2052-170710.1002/prp2.874https://doaj.org/article/b804592a5ce74d749d7cb7315b7cacf72021-10-01T00:00:00Zhttps://doi.org/10.1002/prp2.874https://doaj.org/toc/2052-1707Abstract This study examined the safety, tolerability, and pharmacokinetics (PK) of napabucasin in healthy Asian and non‐Asian participants and investigated the potential for QT/QTc interval prolongation. This five‐part (A–E) study proceeded in a stepwise manner, unless stopping criteria were met. Parts A–D were randomized, double‐blind, placebo‐controlled, and included healthy Asian male and female and non‐Asian male participants. PK parameters were measured following single‐dose napabucasin (80–1200 mg) in the fasted or fed state (Part D). Potential QT/QTc interval prolongation was assessed using digital 12‐lead electrocardiogram (Parts B and C). Part E was open‐label, and examined the PK of single‐dose napabucasin (240–720 mg) in healthy non‐Asian males. Safety and tolerability were measured in Parts A–E. Changes from baseline in the Fridericia‐corrected QT interval (ΔQTcF) and other electrocardiogram parameters were analyzed using a linear mixed‐effects model. Napabucasin was well‐tolerated across the study (n = 70), and no serious adverse events or significant safety issues were reported when administered with or without food. The most frequent treatment‐emergent adverse events were diarrhea and abdominal pain, and these were mild in severity. No prolongation of the QTcF interval was reported following single‐dose napabucasin (240–1200 mg) and changes in other cardiac parameters were negligible. The PK profile of napabucasin was consistent with earlier studies. Single‐dose napabucasin was tolerated in healthy male and female participants, and no significant safety (including no QTcF prolongation) or tolerability issues were identified, irrespective of food intake. Clinical studies of napabucasin in advanced cancers are ongoing.Naoto NodaTakeshi TakagakiYasuhide YodoYuzo HoribuchiShuichi IinoShunji MatsukiYoichiro OgamaHiroyoshi KakuyamaWileyarticleAsianhealthy volunteersnapabucasinnon‐AsianpharmacokineticsQT/QTc intervalTherapeutics. PharmacologyRM1-950ENPharmacology Research & Perspectives, Vol 9, Iss 5, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Asian healthy volunteers napabucasin non‐Asian pharmacokinetics QT/QTc interval Therapeutics. Pharmacology RM1-950
spellingShingle	Asian healthy volunteers napabucasin non‐Asian pharmacokinetics QT/QTc interval Therapeutics. Pharmacology RM1-950 Naoto Noda Takeshi Takagaki Yasuhide Yodo Yuzo Horibuchi Shuichi Iino Shunji Matsuki Yoichiro Ogama Hiroyoshi Kakuyama Effects of a reactive oxygen species generator, napabucasin (BBI608), on tolerability, safety, pharmacokinetics, and QT/QTc interval in healthy volunteers
description	Abstract This study examined the safety, tolerability, and pharmacokinetics (PK) of napabucasin in healthy Asian and non‐Asian participants and investigated the potential for QT/QTc interval prolongation. This five‐part (A–E) study proceeded in a stepwise manner, unless stopping criteria were met. Parts A–D were randomized, double‐blind, placebo‐controlled, and included healthy Asian male and female and non‐Asian male participants. PK parameters were measured following single‐dose napabucasin (80–1200 mg) in the fasted or fed state (Part D). Potential QT/QTc interval prolongation was assessed using digital 12‐lead electrocardiogram (Parts B and C). Part E was open‐label, and examined the PK of single‐dose napabucasin (240–720 mg) in healthy non‐Asian males. Safety and tolerability were measured in Parts A–E. Changes from baseline in the Fridericia‐corrected QT interval (ΔQTcF) and other electrocardiogram parameters were analyzed using a linear mixed‐effects model. Napabucasin was well‐tolerated across the study (n = 70), and no serious adverse events or significant safety issues were reported when administered with or without food. The most frequent treatment‐emergent adverse events were diarrhea and abdominal pain, and these were mild in severity. No prolongation of the QTcF interval was reported following single‐dose napabucasin (240–1200 mg) and changes in other cardiac parameters were negligible. The PK profile of napabucasin was consistent with earlier studies. Single‐dose napabucasin was tolerated in healthy male and female participants, and no significant safety (including no QTcF prolongation) or tolerability issues were identified, irrespective of food intake. Clinical studies of napabucasin in advanced cancers are ongoing.
format	article
author	Naoto Noda Takeshi Takagaki Yasuhide Yodo Yuzo Horibuchi Shuichi Iino Shunji Matsuki Yoichiro Ogama Hiroyoshi Kakuyama
author_facet	Naoto Noda Takeshi Takagaki Yasuhide Yodo Yuzo Horibuchi Shuichi Iino Shunji Matsuki Yoichiro Ogama Hiroyoshi Kakuyama
author_sort	Naoto Noda
title	Effects of a reactive oxygen species generator, napabucasin (BBI608), on tolerability, safety, pharmacokinetics, and QT/QTc interval in healthy volunteers
title_short	Effects of a reactive oxygen species generator, napabucasin (BBI608), on tolerability, safety, pharmacokinetics, and QT/QTc interval in healthy volunteers
title_full	Effects of a reactive oxygen species generator, napabucasin (BBI608), on tolerability, safety, pharmacokinetics, and QT/QTc interval in healthy volunteers
title_fullStr	Effects of a reactive oxygen species generator, napabucasin (BBI608), on tolerability, safety, pharmacokinetics, and QT/QTc interval in healthy volunteers
title_full_unstemmed	Effects of a reactive oxygen species generator, napabucasin (BBI608), on tolerability, safety, pharmacokinetics, and QT/QTc interval in healthy volunteers
title_sort	effects of a reactive oxygen species generator, napabucasin (bbi608), on tolerability, safety, pharmacokinetics, and qt/qtc interval in healthy volunteers
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/b804592a5ce74d749d7cb7315b7cacf7
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Effects of a reactive oxygen species generator, napabucasin (BBI608), on tolerability, safety, pharmacokinetics, and QT/QTc interval in healthy volunteers

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