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Safety, tolerability, and pharmacokinetics of AL-335 in healthy volunteers and hepatitis C virus-infected subjects
- Source :
- PLoS ONE, Vol 13, Iss 10, p e0204974 (2018), PLoS ONE
- Publication Year :
- 2018
- Publisher :
- Public Library of Science (PLoS), 2018.
-
Abstract
- 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 HCV-RNA 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.
- Subjects :
- RNA viruses
Liver Cirrhosis
Male
0301 basic medicine
Cirrhosis
lcsh:Medicine
Hepacivirus
medicine.disease_cause
Gastroenterology
law.invention
Electrocardiography
0302 clinical medicine
Drug Metabolism
Randomized controlled trial
law
Medicine and Health Sciences
Oral Administration
lcsh:Science
Pathology and laboratory medicine
Routes of Administration
media_common
Alanine
Multidisciplinary
Hepatitis C virus
Pharmaceutics
Liver Diseases
Half-life
Medical microbiology
Middle Aged
Hepatitis C
Dose–response relationship
Bioassays and Physiological Analysis
Viruses
RNA, Viral
Female
030211 gastroenterology & hepatology
Pathogens
Research Article
Half-Life
Adult
Drug
medicine.medical_specialty
Genotype
media_common.quotation_subject
Gastroenterology and Hepatology
Research and Analysis Methods
Placebo
Microbiology
Antiviral Agents
Beverages
03 medical and health sciences
Drug Therapy
Double-Blind Method
Pharmacokinetics
Internal medicine
medicine
Humans
Uridine
Nutrition
Pharmacology
Biology and life sciences
Flaviviruses
Tea
Dose-Response Relationship, Drug
business.industry
Electrophysiological Techniques
lcsh:R
Organisms
Viral pathogens
Placebo Effect
medicine.disease
Hepatitis viruses
Microbial pathogens
Diet
030104 developmental biology
Phosphoramides
lcsh:Q
Cardiac Electrophysiology
business
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 13
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....e968101369f61e92a7a720f50340e63a