Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients.

Abstract

BACKGROUND & AIMS:

The search for targeted anti-hepatitis C virus (HCV) drugs is driven by the adverse effect profile and limited efficacy of the current standard of care (pegylated interferon-alpha/ribavirin). In a first-in-human trial, we tested the safety, tolerability, and pharmacokinetics of the macrocyclic HCV NS3/4A protease inhibitor TMC435 in healthy volunteers, followed by HCV genotype 1-infected patients to assess antiviral activity.

METHODS:

The TMC435350-C101 study was a phase I, randomized, double-blind, placebo-controlled trial in 49 healthy volunteers, followed by an open-label, nonplacebo-controlled panel in 6 genotype 1 hepatitis C patients. Healthy volunteers received oral, single, ascending doses (up to 600 mg) or 5-day multiple ascending doses (200 mg twice daily or 100, 200, or 400 mg once daily). Patients received 200 mg once daily for 5 days. Pharmacokinetics and safety were evaluated for all panels, and plasma HCV-RNA levels were determined in patients.

RESULTS:

There were no serious adverse events, no grade 3 reactions, and no treatment-related discontinuations; pharmacokinetics supported a once daily dosing regimen. Plasma HCV-RNA levels dropped rapidly in all patients, with a median maximal reduction of 3.9-log(10) IU/mL and a median of 6 days to maximal reduction. The initial steep reduction of HCV-RNA (median 3.5-log(10) IU/mL at day 3) was followed by a more gradual decline that was maintained over the dosing period. No viral breakthroughs (>1-log(10) IU/mL HCV-RNA increase from nadir) were observed during treatment nor in the 3 days posttreatment; HCV-RNA returned to pretreatment levels by week 4.

CONCLUSIONS:

Once daily TMC435 given orally was generally safe and well tolerated and demonstrated potent antiviral activity.

• Authors: Henk W Reesink, Gregory C Fanning, Khalid Abou Farha, Christine Weegink, André Van Vliet, Gerben Van 't Klooster, Oliver Lenz, Fatima Aharchi, Kris Mariën, Pieter Van Remoortere, Herman de Kock, Fabrice Broeckaert, Paul Meyvisch, Els Van Beirendonck, Kenneth Simmen, René Verloes
• Journal: Gastroenterology (Gastroenterology) Vol. 138 Issue 3 Pg. 913-21 (Mar 2010) ISSN: 1528-0012 [Electronic] United States
• PMID: 19852962 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antiviral Agents
• DNA, Viral
• Heterocyclic Compounds, 3-Ring
• NS3 protein, hepatitis C virus
• Protease Inhibitors
• RNA, Viral
• Sulfonamides
• Viral Nonstructural Proteins
• Simeprevir

Topics

• Administration, Oral
• Adult
• Antiviral Agents (administration & dosage, adverse effects, pharmacokinetics)
• DNA, Viral (analysis)
• Double-Blind Method
• Drug Administration Schedule
• Female
• Genotype
• Hepacivirus (drug effects, enzymology, genetics)
• Hepatitis C (diagnosis, drug therapy)
• Heterocyclic Compounds, 3-Ring (administration & dosage, adverse effects, pharmacokinetics)
• Humans
• Male
• Middle Aged
• Protease Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• RNA, Viral (blood)
• Simeprevir
• Sulfonamides (administration & dosage, adverse effects, pharmacokinetics)
• Time Factors
• Treatment Outcome
• Viral Load (drug effects)
• Viral Nonstructural Proteins (antagonists & inhibitors, genetics)
• Young Adult