Mallalieu N.L.,Hoffmann-La Roche |
Mallalieu N.L.,Roche Holding AG |
Rahimy M.H.,Anadys Pharmaceuticals |
Crowley C.A.,Anadys Pharmaceuticals |
And 3 more authors.
Clinical Therapeutics | Year: 2014
Purpose: New antiviral agents with activity against hepatitis C virus (HCV) are needed to optimize treatment for chronic hepatitis C (CHC). We evaluated the pharmacokinetics of setrobuvir (a non-nucleoside HCV polymerase inhibitor) in healthy volunteers (study 1 & 2) and its antiviral efficacy in patients with genotype 1, noncirrhotic treatment-naive CHC (study 3). Methods: Three studies investigated the pharmacokinetics and pharmacodynamics of setrobuvir. First, sequential cohorts of volunteers were randomly assigned to receive single oral doses of setrobuvir 400 to 3000 mg or placebo in a double-blind, ascending dose study. In the second study, volunteers were randomly assigned to receive multiple doses of setrobuvir (400 or 800 mg once daily [QD] or 600 mg twice a day [BID]). In the third study, patients with genotype 1 CHC received setrobuvir (200, 400, or 800 mg) or placebo BID for 3 days. Findings: After single doses of setrobuvir (400-3000 mg) to volunteers in a fasted state, peak Cmax and AUC0-∞ increased in a less than dose-proportional manner. The mean apparent t1/2z ranged from 22.0 to 31.3 hours and was not dose related. Cmax and AUC increased significantly (4.3- and 6.3-fold, respectively) in volunteers who received 2000 mg with a high-fat meal versus fasting. After multiple oral doses, steady state was achieved after 7 days of dosing (400 or 800 mg QD and 600 mg BID) and accumulation was dose-independent. Mean day 14 plasma exposure increased in a less than dose-proportional manner in volunteers who received 400 and 800 mg QD, but it was more than dose-proportional in volunteers receiving 600 mg BID. Dose did not affect the mean t1/2z (range, 24.1-26.6 hours), apparent oral clearance (0.254-0.516 L/h), or apparent volume of distribution (9.60-18.1 L). In patients with CHC, dose-related reductions in HCV RNA concentration were apparent within 24 hours of the start of treatment. Reductions from baseline to the end of treatment (day 3) in patients treated with setrobuvir 200, 400, and 800 mg BID were -2.1, -2.2, and -2.9 log10 IU/mL, respectively (vs ≤0.1 log10 IU/mL with placebo). Reductions in HCV RNA were greater in patients with genotype 1b (range, -2.7 to -3.1 log10 IU/mL) than in patients with genotype 1a (range, -1.3 to -2.7 log10 IU/mL). Setrobuvir was well tolerated, with no serious adverse events. Implications: The steady state pharmacokinetics of setrobuvir appear to be dose proportional, and setrobuvir produces a mean reduction of 2.9 log10 IU/mL in HCV RNA over 3 days in patients with genotype 1 (a and b) treated with 800 mg BID. ClinicalTrials.gov identifier: NCT00782353. © 2014 Elsevier HS Journals, Inc. All rights reserved.
Gobbi A.,Anadys Pharmaceuticals |
Lardy M.,Anadys Pharmaceuticals |
Kim S.H.,Anadys Pharmaceuticals |
Ruebsam F.,Anadys Pharmaceuticals |
And 3 more authors.
In Silico Biology | Year: 2011
We present Illuminator, a user-friendly web front end to computational models such as docking and 3D shape similarity calculations. Illuminator was specifically created to allow non-experts to design and submit molecules to computational chemistry programs. As such it provides a simple user interface allowing users to submit jobs starting from a 2D structure. The models provided are pre-optimized by computational chemists for each specific target. We provide an example of how Illuminator was used to prioritize the design of molecular substituents in the Anadys HCV Polymerase (NS5B) project. With 7500 submitted jobs in 1.5 years, Illuminator has allowed project teams at Anadys to accelerate the optimization of novel leads. It has also improved communication between project members and increased demand for computational drug discovery tools. © 2011/2012 - IOS Press and the authors. All rights reserved.