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Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects

BACKGROUND: Aprocitentan is an orally active, dual endothelin (ET) receptor antagonist developed for the treatment of hypertension in which, despite available treatments, a medical need exists for drugs with a new mechanism of action. SUBJECTS AND METHODS: In this study, the single- and multiple-dos...

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Autores principales: Sidharta, Patricia N, Melchior, Meggane, Kankam, Martin K, Dingemanse, Jasper
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435120/
https://www.ncbi.nlm.nih.gov/pubmed/30962677
http://dx.doi.org/10.2147/DDDT.S199051
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author Sidharta, Patricia N
Melchior, Meggane
Kankam, Martin K
Dingemanse, Jasper
author_facet Sidharta, Patricia N
Melchior, Meggane
Kankam, Martin K
Dingemanse, Jasper
author_sort Sidharta, Patricia N
collection PubMed
description BACKGROUND: Aprocitentan is an orally active, dual endothelin (ET) receptor antagonist developed for the treatment of hypertension in which, despite available treatments, a medical need exists for drugs with a new mechanism of action. SUBJECTS AND METHODS: In this study, the single- and multiple-dose tolerability, safety, pharmacokinetics (PK), and pharmacodynamics of up to 600 mg (single doses) and 100 mg once a day (qd; multiple doses) of aprocitentan were investigated in healthy male and female subjects. The effect of age on the tolerability and PK parameters was investigated at a dose of 100 mg qd. RESULTS: Aprocitentan was well tolerated across all doses. No serious adverse events (AEs) occurred. The most frequently reported AE was headache. Small increases in body weight were recorded in subjects receiving 100 mg qd. Plasma concentration–time profiles of aprocitentan were similar after single- and multiple-dose administration, and support a qd dosing regimen based on a half-life of 44 hours. After multiple doses, PK was dose proportional. Accumulation at steady state, reached by Day 8, was 3-fold. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, and fed and fasted conditions were observed. Plasma ET-1 concentrations, reflecting ET(B) receptor antagonism, significantly increased with doses ≥25 mg. Time-matched analysis of electrocardiogram (ECG) parameters did not suggest drug-induced ECG effects. Exposure–response analysis indicated no QTc prolongations at plasma levels up to 10 µg/mL. CONCLUSION: Aprocitentan was well tolerated in healthy subjects with a PK profile favorable for qd dosing.
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spelling pubmed-64351202019-04-08 Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects Sidharta, Patricia N Melchior, Meggane Kankam, Martin K Dingemanse, Jasper Drug Des Devel Ther Original Research BACKGROUND: Aprocitentan is an orally active, dual endothelin (ET) receptor antagonist developed for the treatment of hypertension in which, despite available treatments, a medical need exists for drugs with a new mechanism of action. SUBJECTS AND METHODS: In this study, the single- and multiple-dose tolerability, safety, pharmacokinetics (PK), and pharmacodynamics of up to 600 mg (single doses) and 100 mg once a day (qd; multiple doses) of aprocitentan were investigated in healthy male and female subjects. The effect of age on the tolerability and PK parameters was investigated at a dose of 100 mg qd. RESULTS: Aprocitentan was well tolerated across all doses. No serious adverse events (AEs) occurred. The most frequently reported AE was headache. Small increases in body weight were recorded in subjects receiving 100 mg qd. Plasma concentration–time profiles of aprocitentan were similar after single- and multiple-dose administration, and support a qd dosing regimen based on a half-life of 44 hours. After multiple doses, PK was dose proportional. Accumulation at steady state, reached by Day 8, was 3-fold. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, and fed and fasted conditions were observed. Plasma ET-1 concentrations, reflecting ET(B) receptor antagonism, significantly increased with doses ≥25 mg. Time-matched analysis of electrocardiogram (ECG) parameters did not suggest drug-induced ECG effects. Exposure–response analysis indicated no QTc prolongations at plasma levels up to 10 µg/mL. CONCLUSION: Aprocitentan was well tolerated in healthy subjects with a PK profile favorable for qd dosing. Dove Medical Press 2019-03-22 /pmc/articles/PMC6435120/ /pubmed/30962677 http://dx.doi.org/10.2147/DDDT.S199051 Text en © 2019 Sidharta et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Sidharta, Patricia N
Melchior, Meggane
Kankam, Martin K
Dingemanse, Jasper
Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects
title Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects
title_full Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects
title_fullStr Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects
title_full_unstemmed Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects
title_short Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects
title_sort single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435120/
https://www.ncbi.nlm.nih.gov/pubmed/30962677
http://dx.doi.org/10.2147/DDDT.S199051
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