Safety, tolerability, and pharmacokinetics of AL-335 in healthy volunteers and hepatitis C virus-infected subjects

McClure 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

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MCCLURE, 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

Numărul 10(13) / 2018 / ISSN 1932-6203

Safety, tolerability, and pharmacokinetics of AL-335 in healthy volunteers and hepatitis C virus-infected subjects

DOI:https://doi.org/10.1371/journal.pone.0204974

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McClure Matthew W.¹, Berliba Elina², Tsertsvadze Tengiz³, Streinu-Cercel Adrian⁴, Vijgen Leen⁵, Astruc Beatrice⁶, Patat Alain A.⁶, Westland Christopher E.¹, Chanda Sushmita¹, Zhang Qingling¹, Kakuda Thomas¹, Vuong Jennifer¹, Khorlin Nick¹, Beigelman Leonid N.¹, Blatt Lawrence Mitchell¹, Fry John¹

¹ Alios BioPharma, Inc.,
² ”Nicolae Testemițanu” State University of Medicine and Pharmacy,
³ AIDS and Clinical Immunology Research Center of Georgia,
⁴ University of Medicine and Pharmacy “Carol Davilla”, Bucharest,
⁵ Janssen Research & Development BE, Beerse,
⁶ Biotrial

Disponibil în IBN: 5 decembrie 2018

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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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