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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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| 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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DataCite XML Export
<?xml version='1.0' encoding='utf-8'?> <resource xmlns:xsi='http://www.w3.org/2001/XMLSchema-instance' xmlns='http://datacite.org/schema/kernel-3' xsi:schemaLocation='http://datacite.org/schema/kernel-3 http://schema.datacite.org/meta/kernel-3/metadata.xsd'> <identifier identifierType='DOI'>10.1371/journal.pone.0204974</identifier> <creators> <creator> <creatorName>McClure, M.</creatorName> <affiliation>Alios BioPharma, Inc., Statele Unite ale Americii</affiliation> </creator> <creator> <creatorName>Berliba, E.T.</creatorName> <affiliation>Universitatea de Stat de Medicină şi Farmacie „Nicolae Testemiţanu“, Moldova, Republica</affiliation> </creator> <creator> <creatorName>Tsertsvadze, T.</creatorName> <affiliation>AIDS and Clinical Immunology Research Center of Georgia, Georgia</affiliation> </creator> <creator> <creatorName>Streinu-Cercel, A.</creatorName> <affiliation>Universitatea de Medicină şi Farmacie „Carol Davila“, România</affiliation> </creator> <creator> <creatorName>Vijgen, L.</creatorName> <affiliation>Janssen Research & Development BE, Beerse, Belgia</affiliation> </creator> <creator> <creatorName>Astruc, B.</creatorName> <affiliation>Biotrial, Franţa</affiliation> </creator> <creator> <creatorName>Patat, A.</creatorName> <affiliation>Biotrial, Franţa</affiliation> </creator> <creator> <creatorName>Westland, C.</creatorName> <affiliation>Alios BioPharma, Inc., Statele Unite ale Americii</affiliation> </creator> <creator> <creatorName>Chanda, S.</creatorName> <affiliation>Alios BioPharma, Inc., Statele Unite ale Americii</affiliation> </creator> <creator> <creatorName>Zhang, Q.</creatorName> <affiliation>Alios BioPharma, Inc., Statele Unite ale Americii</affiliation> </creator> <creator> <creatorName>Kakuda, T.</creatorName> <affiliation>Alios BioPharma, Inc., Statele Unite ale Americii</affiliation> </creator> <creator> <creatorName>Vuong, J.</creatorName> <affiliation>Alios BioPharma, Inc., Statele Unite ale Americii</affiliation> </creator> <creator> <creatorName>Khorlin, N.</creatorName> <affiliation>Alios BioPharma, Inc., Statele Unite ale Americii</affiliation> </creator> <creator> <creatorName>Beigelman, L.</creatorName> <affiliation>Alios BioPharma, Inc., Statele Unite ale Americii</affiliation> </creator> <creator> <creatorName>Blatt, L.</creatorName> <affiliation>Alios BioPharma, Inc., Statele Unite ale Americii</affiliation> </creator> <creator> <creatorName>Fry, J.</creatorName> <affiliation>Alios BioPharma, Inc., Statele Unite ale Americii</affiliation> </creator> </creators> <titles> <title xml:lang='en'>Safety, tolerability, and pharmacokinetics of AL-335 in healthy volunteers and hepatitis C virus-infected subjects</title> </titles> <publisher>Instrumentul Bibliometric National</publisher> <publicationYear>2018</publicationYear> <relatedIdentifier relatedIdentifierType='ISSN' relationType='IsPartOf'>1932-6203</relatedIdentifier> <dates> <date dateType='Issued'>2018-10-15</date> </dates> <resourceType resourceTypeGeneral='Text'>Journal article</resourceType> <descriptions> <description xml:lang='en' descriptionType='Abstract'><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></description> </descriptions> <formats> <format>uri</format> </formats> </resource>
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