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Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects

This Phase I, open‐label, two‐group, fixed‐sequence study evaluated the pharmacokinetics and safety of AL‐335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL‐335 800 mg once daily (QD) (days 1‐3, 11‐13, and 21‐23), simeprevir 150 mg QD (days 4‐23), and odalasvir 150 mg (...

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Autores principales: Kakuda, Thomas N., McClure, Matthew W., Westland, Christopher, Vuong, Jennifer, Homery, Marie‐Claude, Poizat, Gwendoline, Viguerie, Laure, Denot, Caroline, Patat, Alain, Zhang, Qingling, Hui, James, Apelian, David, Smith, David B., Chanda, Sushmita M., Fry, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927802/
https://www.ncbi.nlm.nih.gov/pubmed/29736243
http://dx.doi.org/10.1002/prp2.395
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author Kakuda, Thomas N.
McClure, Matthew W.
Westland, Christopher
Vuong, Jennifer
Homery, Marie‐Claude
Poizat, Gwendoline
Viguerie, Laure
Denot, Caroline
Patat, Alain
Zhang, Qingling
Hui, James
Apelian, David
Smith, David B.
Chanda, Sushmita M.
Fry, John
author_facet Kakuda, Thomas N.
McClure, Matthew W.
Westland, Christopher
Vuong, Jennifer
Homery, Marie‐Claude
Poizat, Gwendoline
Viguerie, Laure
Denot, Caroline
Patat, Alain
Zhang, Qingling
Hui, James
Apelian, David
Smith, David B.
Chanda, Sushmita M.
Fry, John
author_sort Kakuda, Thomas N.
collection PubMed
description This Phase I, open‐label, two‐group, fixed‐sequence study evaluated the pharmacokinetics and safety of AL‐335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL‐335 800 mg once daily (QD) (days 1‐3, 11‐13, and 21‐23), simeprevir 150 mg QD (days 4‐23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15‐23). Group 2 (n = 16) received the same AL‐335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5‐23) and simeprevir 150 mg QD (days 14‐23). Blood samples were collected to determine plasma concentrations of AL‐335 (prodrug) and its metabolites, ALS‐022399 (monophosphate precursor) and ALS‐022227 (parent nucleoside), odalasvir, and simeprevir. Thirty‐two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL‐335 area under plasma concentration‐time curve over 24 hours (AUC (0‐24 h)) 3‐, 4‐, and 7‐ to 8‐fold, respectively; ALS‐022399 AUC (0‐24 h) increased 2‐, 2‐, and 3‐fold, respectively. Simeprevir had no effect on ALS‐022227 AUC (0‐24 h), whereas odalasvir with/without simeprevir increased ALS‐022227 AUC (0‐24 h) 1.5‐fold. AL‐335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC (0‐24 h) increased 1.5‐ to 2‐fold for both drugs when coadministered irrespective of AL‐335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL‐335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.
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spelling pubmed-59278022018-05-07 Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects Kakuda, Thomas N. McClure, Matthew W. Westland, Christopher Vuong, Jennifer Homery, Marie‐Claude Poizat, Gwendoline Viguerie, Laure Denot, Caroline Patat, Alain Zhang, Qingling Hui, James Apelian, David Smith, David B. Chanda, Sushmita M. Fry, John Pharmacol Res Perspect Original Articles This Phase I, open‐label, two‐group, fixed‐sequence study evaluated the pharmacokinetics and safety of AL‐335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL‐335 800 mg once daily (QD) (days 1‐3, 11‐13, and 21‐23), simeprevir 150 mg QD (days 4‐23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15‐23). Group 2 (n = 16) received the same AL‐335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5‐23) and simeprevir 150 mg QD (days 14‐23). Blood samples were collected to determine plasma concentrations of AL‐335 (prodrug) and its metabolites, ALS‐022399 (monophosphate precursor) and ALS‐022227 (parent nucleoside), odalasvir, and simeprevir. Thirty‐two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL‐335 area under plasma concentration‐time curve over 24 hours (AUC (0‐24 h)) 3‐, 4‐, and 7‐ to 8‐fold, respectively; ALS‐022399 AUC (0‐24 h) increased 2‐, 2‐, and 3‐fold, respectively. Simeprevir had no effect on ALS‐022227 AUC (0‐24 h), whereas odalasvir with/without simeprevir increased ALS‐022227 AUC (0‐24 h) 1.5‐fold. AL‐335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC (0‐24 h) increased 1.5‐ to 2‐fold for both drugs when coadministered irrespective of AL‐335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL‐335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection. John Wiley and Sons Inc. 2018-04-30 /pmc/articles/PMC5927802/ /pubmed/29736243 http://dx.doi.org/10.1002/prp2.395 Text en © 2018 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Kakuda, Thomas N.
McClure, Matthew W.
Westland, Christopher
Vuong, Jennifer
Homery, Marie‐Claude
Poizat, Gwendoline
Viguerie, Laure
Denot, Caroline
Patat, Alain
Zhang, Qingling
Hui, James
Apelian, David
Smith, David B.
Chanda, Sushmita M.
Fry, John
Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects
title Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects
title_full Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects
title_fullStr Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects
title_full_unstemmed Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects
title_short Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects
title_sort pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of al‐335, odalasvir, and simeprevir in healthy subjects
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927802/
https://www.ncbi.nlm.nih.gov/pubmed/29736243
http://dx.doi.org/10.1002/prp2.395
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