Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator

Autor: Alla Arzumanyan, Zhe Chen, Noreen McBrearty, James J. Kohler, Leda Bassit, Mark A. Feitelson, Sijia Tao, Eugene Bichenkov, Selwyn J. Hurwitz, Raymond F. Schinazi, Franck Amblard
Rok vydání: 2021
Předmět:
Zdroj: Viruses, Vol 13, Iss 114, p 114 (2021)
Viruses
Volume 13
Issue 1
ISSN: 1999-4915
DOI: 10.3390/v13010114
Popis: While treatment options are available for hepatitis B virus (HBV), there is currently no cure. Anti-HBV nucleoside analogs and interferon-alpha 2b rarely clear HBV covalently closed circular DNA (cccDNA), requiring lifelong treatment. Recently, we identified GLP-26, a glyoxamide derivative which modulates HBV capsid assembly. The impact of GLP-26 on viral replication and integrated DNA was assessed in an HBV nude mouse model bearing HBV transfected AD38 xenografts. At day 45 post-infection, GLP-26 reduced HBV titers by 2.3&ndash
3 log10 versus infected placebo-treated mice. Combination therapy with GLP-26 and entecavir reduced HBV log10 titers by 4.6-fold versus placebo. Next, we examined the pharmacokinetics (PK) in cynomolgus monkeys administered GLP-26 via IV (1 mg/kg) or PO (5 mg/kg). GLP-26 was found to have 34% oral bioavailability, with a mean input time of 3.17 h. The oral dose produced a mean peak plasma concentration of 380.7 ng/mL, observed 0.67 h after administration (~30-fold >
in vitro EC90 corrected for protein binding), with a mean terminal elimination half-life of 2.4 h and a mean area under the plasma concentration versus time curve of 1660 ng.hr/mL. GLP-26 was 86.7% bound in monkey plasma. Lastly, GLP-26 demonstrated a favorable toxicity profile confirmed in primary human cardiomyocytes. Thus, GLP-26 warrants further preclinical development as an add on to treatment for HBV infection.
Databáze: OpenAIRE
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