ABT-333 is a nonnucleoside NS5B polymerase inhibitor for the treatment of HCV infection. An interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. ABT-333 is currently under clinical trials for the treatment of Hepatitis C.
|Cell lines||HCV replicon cells|
|Preparation method||MTT analysis Both replicon-containing cell lines were maintained in Dulbecco’s modified Eagle’s medium (DMEM) containing 100 IU/ml penicillin, 100 g/ml streptomycin, and 200 g/ml G418 (all from Invitrogen, Carlsbad, CA) with 10% (vol/vol) fetal bovine serum (FBS).TheinhibitoryeffectsofdasabuvironHCVRNAreplication were determined in DMEM containing 5% FBS, with or without 40% human plasma (Bioreclamation, Westbury, NY), by measuring the activity of the luciferase reporter gene. The cells were incubated for 3 days in the presence of dasabuvir and subsequently were lysed and processed according to the manufacturer’s instructions (Promega, Madison, WI). The luciferase activity in the cells was measured using a Victor II luminometer (Perkin-Elmer, Waltham, MA); 50% effective concentration (EC50) values were calculated using nonlinear regression curve fitting to a 4-parameter logistic equation with GraphPad Prism 4 software. EC50s and standard deviations (SDs) were calculated from at least 3 experiments conducted in duplicate. The cytotoxicity of dasabuvir was determined with the colorimetric assay using MTT.|
|Concentrations||Dasabuvir inhibited replication of HCV subgenomic replicons in cell culture assays, with EC50 values of 7.7 and 1.8 nM against genotype 1a (H77) and 1b (Con1), respectively.|
|Incubation time||3 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO 26 mg/mL|
Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1.
Kowdley KV, et al. N Engl J Med. 2014 Jan 16;370(3):222-32. PMID: 24428468.
Exploratory study of oral combination antiviral therapy for hepatitis C.
Poordad F, et al. N Engl J Med. 2013 Jan 3;368(1):45-53. PMID: 23281975.
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