Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates
| Autor: | Scott A, Reisman, Sarabjit S, Gahir, Chun-Yue I, Lee, Joel W, Proksch, Mitsumasa, Sakamoto, Keith W, Ward |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Dose-Response Relationship Drug NF-E2-Related Factor 2 ferritin omaveloxolone Administration Oral Friedreich’s ataxia Triterpenes Nrf2 Macaca fascicularis Structure-Activity Relationship Double-Blind Method Friedreich Ataxia NADPH Animals Humans Female Nqo1 RNA Messenger glutathione pharmacokinetics Original Research |
| Zdroj: | Drug Design, Development and Therapy |
| ISSN: | 1177-8881 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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