Bioequivalence and food effect of a fixed‐dose combination of macitentan and tadalafil: Adaptive design in the COVID‐19 pandemic

Abstract The COVID‐19 pandemic has forced clinical studies to accommodate imposed limitations. In this study, the bioequivalence part could not be conducted as planned. Thus, the aim was to demonstrate bioequivalence, using an adaptive study design, of tadalafil in fixed‐dose combination (FDC) table...

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Autores principales:	Dénes Csonka, Vladislav Fishman, Jaya Natarajan, Hans Stieltjes, Danielle Armas, Victor Dishy, Juan Jose Perez Ruixo
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	bioequivalence fasted fed fixed‐dose combination food effect macitentan Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/31a919ca32f146339e7cacbab7365ba6
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spelling	oai:doaj.org-article:31a919ca32f146339e7cacbab7365ba62021-11-16T13:45:54ZBioequivalence and food effect of a fixed‐dose combination of macitentan and tadalafil: Adaptive design in the COVID‐19 pandemic2052-170710.1002/prp2.846https://doaj.org/article/31a919ca32f146339e7cacbab7365ba62021-10-01T00:00:00Zhttps://doi.org/10.1002/prp2.846https://doaj.org/toc/2052-1707Abstract The COVID‐19 pandemic has forced clinical studies to accommodate imposed limitations. In this study, the bioequivalence part could not be conducted as planned. Thus, the aim was to demonstrate bioequivalence, using an adaptive study design, of tadalafil in fixed‐dose combination (FDC) tablets of macitentan/tadalafil with single macitentan and tadalafil (Canadian‐sourced) tablets and assess the effect of food on FDC tablets in healthy subjects. This Phase 1, single‐center, open‐label, single‐dose, two‐part, two‐period, randomized, crossover study enrolled 62 subjects. Tadalafil bioequivalence as part of FDC of macitentan/tadalafil (10/40 mg) with single‐component tablets of macitentan (10 mg) and tadalafil (40 mg) was determined by pharmacokinetic (PK) assessment under fasted conditions. The effect of food on FDC was evaluated under fed and fasted conditions. Fasted 90% confidence intervals (CIs) for geometric mean ratios (GMRs) were within bioequivalence limits for tadalafil and macitentan. Fed and fasted 90% CIs for area under the curve (AUC) GMR were within bioequivalence limits. However, 90% CIs for maximum plasma concentration (Cmax) GMR for macitentan and tadalafil were outside bioequivalence limits. One FDC‐treated subject experienced a serious adverse event of transient ischemic attack (bioequivalence part). To address pandemic‐imposed limitations, an adaptive study design was implemented to demonstrate that the FDC tablet was bioequivalent to the free combination of macitentan and tadalafil (Canadian‐sourced). No clinically significant differences in PK were determined between fed and fasted conditions; the FDC formulation could be taken irrespective of meals. The FDC formulation under fasted and fed conditions was well tolerated with no clinically relevant differences in safety profiles between the treatment groups. NCT Number: NCT04235270.Dénes CsonkaVladislav FishmanJaya NatarajanHans StieltjesDanielle ArmasVictor DishyJuan Jose Perez RuixoWileyarticlebioequivalencefastedfedfixed‐dose combinationfood effectmacitentanTherapeutics. PharmacologyRM1-950ENPharmacology Research & Perspectives, Vol 9, Iss 5, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	bioequivalence fasted fed fixed‐dose combination food effect macitentan Therapeutics. Pharmacology RM1-950
spellingShingle	bioequivalence fasted fed fixed‐dose combination food effect macitentan Therapeutics. Pharmacology RM1-950 Dénes Csonka Vladislav Fishman Jaya Natarajan Hans Stieltjes Danielle Armas Victor Dishy Juan Jose Perez Ruixo Bioequivalence and food effect of a fixed‐dose combination of macitentan and tadalafil: Adaptive design in the COVID‐19 pandemic
description	Abstract The COVID‐19 pandemic has forced clinical studies to accommodate imposed limitations. In this study, the bioequivalence part could not be conducted as planned. Thus, the aim was to demonstrate bioequivalence, using an adaptive study design, of tadalafil in fixed‐dose combination (FDC) tablets of macitentan/tadalafil with single macitentan and tadalafil (Canadian‐sourced) tablets and assess the effect of food on FDC tablets in healthy subjects. This Phase 1, single‐center, open‐label, single‐dose, two‐part, two‐period, randomized, crossover study enrolled 62 subjects. Tadalafil bioequivalence as part of FDC of macitentan/tadalafil (10/40 mg) with single‐component tablets of macitentan (10 mg) and tadalafil (40 mg) was determined by pharmacokinetic (PK) assessment under fasted conditions. The effect of food on FDC was evaluated under fed and fasted conditions. Fasted 90% confidence intervals (CIs) for geometric mean ratios (GMRs) were within bioequivalence limits for tadalafil and macitentan. Fed and fasted 90% CIs for area under the curve (AUC) GMR were within bioequivalence limits. However, 90% CIs for maximum plasma concentration (Cmax) GMR for macitentan and tadalafil were outside bioequivalence limits. One FDC‐treated subject experienced a serious adverse event of transient ischemic attack (bioequivalence part). To address pandemic‐imposed limitations, an adaptive study design was implemented to demonstrate that the FDC tablet was bioequivalent to the free combination of macitentan and tadalafil (Canadian‐sourced). No clinically significant differences in PK were determined between fed and fasted conditions; the FDC formulation could be taken irrespective of meals. The FDC formulation under fasted and fed conditions was well tolerated with no clinically relevant differences in safety profiles between the treatment groups. NCT Number: NCT04235270.
format	article
author	Dénes Csonka Vladislav Fishman Jaya Natarajan Hans Stieltjes Danielle Armas Victor Dishy Juan Jose Perez Ruixo
author_facet	Dénes Csonka Vladislav Fishman Jaya Natarajan Hans Stieltjes Danielle Armas Victor Dishy Juan Jose Perez Ruixo
author_sort	Dénes Csonka
title	Bioequivalence and food effect of a fixed‐dose combination of macitentan and tadalafil: Adaptive design in the COVID‐19 pandemic
title_short	Bioequivalence and food effect of a fixed‐dose combination of macitentan and tadalafil: Adaptive design in the COVID‐19 pandemic
title_full	Bioequivalence and food effect of a fixed‐dose combination of macitentan and tadalafil: Adaptive design in the COVID‐19 pandemic
title_fullStr	Bioequivalence and food effect of a fixed‐dose combination of macitentan and tadalafil: Adaptive design in the COVID‐19 pandemic
title_full_unstemmed	Bioequivalence and food effect of a fixed‐dose combination of macitentan and tadalafil: Adaptive design in the COVID‐19 pandemic
title_sort	bioequivalence and food effect of a fixed‐dose combination of macitentan and tadalafil: adaptive design in the covid‐19 pandemic
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/31a919ca32f146339e7cacbab7365ba6
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Bioequivalence and food effect of a fixed‐dose combination of macitentan and tadalafil: Adaptive design in the COVID‐19 pandemic

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