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Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates

BACKGROUND: Omaveloxolone is a synthetic oleanane triterpenoid that pharmacologically activates Nrf2, a master transcription factor that regulates genes with antioxidative, anti-inflammatory, and mitochondrial bioenergetic properties, and is being evaluated in patients with Friedreich’s ataxia. METH...

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Autores principales: Reisman, Scott A, Gahir, Sarabjit S, Lee, Chun-Yue I, Proksch, Joel W, Sakamoto, Mitsumasa, Ward, Keith W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475100/
https://www.ncbi.nlm.nih.gov/pubmed/31118567
http://dx.doi.org/10.2147/DDDT.S193889
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author Reisman, Scott A
Gahir, Sarabjit S
Lee, Chun-Yue I
Proksch, Joel W
Sakamoto, Mitsumasa
Ward, Keith W
author_facet Reisman, Scott A
Gahir, Sarabjit S
Lee, Chun-Yue I
Proksch, Joel W
Sakamoto, Mitsumasa
Ward, Keith W
author_sort Reisman, Scott A
collection PubMed
description BACKGROUND: Omaveloxolone is a synthetic oleanane triterpenoid that pharmacologically activates Nrf2, a master transcription factor that regulates genes with antioxidative, anti-inflammatory, and mitochondrial bioenergetic properties, and is being evaluated in patients with Friedreich’s ataxia. METHODS: The present study evaluated the pharmacokinetics (PK) and tissue distribution of omaveloxolone in monkeys after single and multiple oral doses, and then compared these data to initial results in Friedreich’s ataxia patients. Pharmacodynamic (PD) evaluations in monkeys consisted of Nrf2 target gene mRNA expression in peripheral blood mononuclear cells (PBMCs), liver, lung, and brain. A PK/PD model was generated with the monkey data, and used to further evaluate the Friedreich’s ataxia patient PK profile. RESULTS: Oral administration of omaveloxolone to monkeys was associated with dose-linear plasma PK and readily measureable and dose-proportional concentrations in liver, lung, and brain. Dose-dependent induction of Nrf2 target genes in PBMCs and tissues was also observed. Clinically, oral administration of omaveloxolone to Friedreich’s ataxia patients at incremental doses from 2.5 to 300 mg produced dose-proportional systemic exposures. Clinical doses of at least 80 mg were associated with meaningful improvements in neurological function in patients and generated plasma omaveloxolone concentrations consistent with those significantly inducing Nrf2 target genes in monkeys, as shown with the monkey PK/PD model. CONCLUSION: Overall, the monkey data demonstrate a well-characterized and dose-proportional PK and tissue distribution profile after oral administration of omaveloxolone, which was associated with Nrf2 activation. Further, systemic exposures to omaveloxolone that produce Nrf2 activation in monkeys were readily achievable in Friedreich’s ataxia patients after oral administration.
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spelling pubmed-64751002019-05-22 Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates Reisman, Scott A Gahir, Sarabjit S Lee, Chun-Yue I Proksch, Joel W Sakamoto, Mitsumasa Ward, Keith W Drug Des Devel Ther Original Research BACKGROUND: Omaveloxolone is a synthetic oleanane triterpenoid that pharmacologically activates Nrf2, a master transcription factor that regulates genes with antioxidative, anti-inflammatory, and mitochondrial bioenergetic properties, and is being evaluated in patients with Friedreich’s ataxia. METHODS: The present study evaluated the pharmacokinetics (PK) and tissue distribution of omaveloxolone in monkeys after single and multiple oral doses, and then compared these data to initial results in Friedreich’s ataxia patients. Pharmacodynamic (PD) evaluations in monkeys consisted of Nrf2 target gene mRNA expression in peripheral blood mononuclear cells (PBMCs), liver, lung, and brain. A PK/PD model was generated with the monkey data, and used to further evaluate the Friedreich’s ataxia patient PK profile. RESULTS: Oral administration of omaveloxolone to monkeys was associated with dose-linear plasma PK and readily measureable and dose-proportional concentrations in liver, lung, and brain. Dose-dependent induction of Nrf2 target genes in PBMCs and tissues was also observed. Clinically, oral administration of omaveloxolone to Friedreich’s ataxia patients at incremental doses from 2.5 to 300 mg produced dose-proportional systemic exposures. Clinical doses of at least 80 mg were associated with meaningful improvements in neurological function in patients and generated plasma omaveloxolone concentrations consistent with those significantly inducing Nrf2 target genes in monkeys, as shown with the monkey PK/PD model. CONCLUSION: Overall, the monkey data demonstrate a well-characterized and dose-proportional PK and tissue distribution profile after oral administration of omaveloxolone, which was associated with Nrf2 activation. Further, systemic exposures to omaveloxolone that produce Nrf2 activation in monkeys were readily achievable in Friedreich’s ataxia patients after oral administration. Dove Medical Press 2019-04-17 /pmc/articles/PMC6475100/ /pubmed/31118567 http://dx.doi.org/10.2147/DDDT.S193889 Text en © 2019 Reisman 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
Reisman, Scott A
Gahir, Sarabjit S
Lee, Chun-Yue I
Proksch, Joel W
Sakamoto, Mitsumasa
Ward, Keith W
Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates
title Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates
title_full Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates
title_fullStr Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates
title_full_unstemmed Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates
title_short Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates
title_sort pharmacokinetics and pharmacodynamics of the novel nrf2 activator omaveloxolone in primates
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475100/
https://www.ncbi.nlm.nih.gov/pubmed/31118567
http://dx.doi.org/10.2147/DDDT.S193889
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