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 SM ISO690:2012MCCLURE, Matthew W., BERLIBA, Elina, TSERTSVADZE, Tengiz, STREINU-CERCEL, Adrian, VIJGEN, Leen, ASTRUC, Beatrice, PATAT, Alain A., WESTLAND, Christopher E., CHANDA, Sushmita, ZHANG, Qingling, KAKUDA, Thomas, VUONG, Jennifer, KHORLIN, Nick, BEIGELMAN, Leonid N., BLATT, Lawrence Mitchell, FRY, John. Safety, tolerability, and pharmacokinetics of AL-335 in healthy volunteers and hepatitis C virus-infected subjects. In: PLoS ONE, 2018, nr. 10(13), p. 0. ISSN 1932-6203. DOI: https://doi.org/10.1371/journal.pone.0204974 |
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  PLoS ONE |
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| Numărul 10(13) / 2018 / ISSN 1932-6203 | |
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| DOI:https://doi.org/10.1371/journal.pone.0204974 | |
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Background The nucleotide analog AL-335 is a pangenotypic hepatitis C virus (HCV) nonstructural protein (NS)5B inhibitor being evaluated as treatment for chronic HCV infection. Methods This three-part randomized, double-blind study evaluated the safety and pharmacokinetics of single and multiple ascending oral doses of AL-335. Healthy volunteers (HVs) received single doses of AL-335 (100-1,200 mg) or placebo in a fasted or fed (400 mg) state. Non-cirrhotic subjects (HCV genotype [GT]1-4) and GT1-infected subjects with Child Pugh A cirrhosis received multiple doses of AL-335 (400, 800, 1,200 mg) or placebo once daily (QD) for 7 days. Results Forty-eight HVs and 64 subjects with HCV GT1-4 were randomized and received treatment. AL-335 was well tolerated in HVs and HCV-infected subjects with/without cirrhosis. AL-335 was rapidly absorbed and converted to the metabolites ALS-022399 and ALS-022227. ALS- 022227 exposure increased less than dose-proportionally and was unaffected by food, while AL-335 and ALS-022399 exposure increased with food by 85% and 50%, respectively, in HVs. Rapid and dose-dependent reductions in HCV-RNA were observed in GT1-infected subjects. In non-cirrhotic, GT1-4-infected subjects receiving AL-335 800 mg QD, potent antiviral activity was observed, regardless of genotype (mean maximum reductions in HCVRNA of 4.0-4.8 log10 IU/mL). The same dose in GT1-infected cirrhotic subjects resulted in a 3.5 log10 IU/mL mean maximum reduction in HCV-RNA. Conclusions AL-335 was well tolerated when administered as single and multiple doses, with an acceptable pharmacokinetic profile. The drug also demonstrated potent antiviral activity in HCV GT1-4-infected subjects, including GT1-infected subjects with cirrhosis. |
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<?xml version='1.0' encoding='utf-8'?> <oai_dc:dc xmlns:dc='http://purl.org/dc/elements/1.1/' xmlns:oai_dc='http://www.openarchives.org/OAI/2.0/oai_dc/' xmlns:xsi='http://www.w3.org/2001/XMLSchema-instance' xsi:schemaLocation='http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd'> <dc:creator>McClure, M.</dc:creator> <dc:creator>Berliba, E.T.</dc:creator> <dc:creator>Tsertsvadze, T.</dc:creator> <dc:creator>Streinu-Cercel, A.</dc:creator> <dc:creator>Vijgen, L.</dc:creator> <dc:creator>Astruc, B.</dc:creator> <dc:creator>Patat, A.</dc:creator> <dc:creator>Westland, C.</dc:creator> <dc:creator>Chanda, S.</dc:creator> <dc:creator>Zhang, Q.</dc:creator> <dc:creator>Kakuda, T.</dc:creator> <dc:creator>Vuong, J.</dc:creator> <dc:creator>Khorlin, N.</dc:creator> <dc:creator>Beigelman, L.</dc:creator> <dc:creator>Blatt, L.</dc:creator> <dc:creator>Fry, J.</dc:creator> <dc:date>2018-10-15</dc:date> <dc:description xml:lang='en'><p>Background The nucleotide analog AL-335 is a pangenotypic hepatitis C virus (HCV) nonstructural protein (NS)5B inhibitor being evaluated as treatment for chronic HCV infection. Methods This three-part randomized, double-blind study evaluated the safety and pharmacokinetics of single and multiple ascending oral doses of AL-335. Healthy volunteers (HVs) received single doses of AL-335 (100-1,200 mg) or placebo in a fasted or fed (400 mg) state. Non-cirrhotic subjects (HCV genotype [GT]1-4) and GT1-infected subjects with Child Pugh A cirrhosis received multiple doses of AL-335 (400, 800, 1,200 mg) or placebo once daily (QD) for 7 days. Results Forty-eight HVs and 64 subjects with HCV GT1-4 were randomized and received treatment. AL-335 was well tolerated in HVs and HCV-infected subjects with/without cirrhosis. AL-335 was rapidly absorbed and converted to the metabolites ALS-022399 and ALS-022227. ALS- 022227 exposure increased less than dose-proportionally and was unaffected by food, while AL-335 and ALS-022399 exposure increased with food by 85% and 50%, respectively, in HVs. Rapid and dose-dependent reductions in HCV-RNA were observed in GT1-infected subjects. In non-cirrhotic, GT1-4-infected subjects receiving AL-335 800 mg QD, potent antiviral activity was observed, regardless of genotype (mean maximum reductions in HCVRNA of 4.0-4.8 log10 IU/mL). The same dose in GT1-infected cirrhotic subjects resulted in a 3.5 log10 IU/mL mean maximum reduction in HCV-RNA. Conclusions AL-335 was well tolerated when administered as single and multiple doses, with an acceptable pharmacokinetic profile. The drug also demonstrated potent antiviral activity in HCV GT1-4-infected subjects, including GT1-infected subjects with cirrhosis.</p></dc:description> <dc:identifier>10.1371/journal.pone.0204974</dc:identifier> <dc:source>PLoS ONE 13 (10) 0-0</dc:source> <dc:title>Safety, tolerability, and pharmacokinetics of AL-335 in healthy volunteers and hepatitis C virus-infected subjects</dc:title> <dc:type>info:eu-repo/semantics/article</dc:type> </oai_dc:dc>
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