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. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
RCT Entities:
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-infectedpatients 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. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Authors: J de Bruijne; J van de Wetering de Rooij; A A van Vliet; X J Zhou; M F Temam; J Molles; J Chen; K Pietropaolo; J Z Sullivan-Bólyai; D Mayers; H W Reesink Journal: Antimicrob Agents Chemother Date: 2012-06-04 Impact factor: 5.191
Authors: Oliver Lenz; Thierry Verbinnen; Tse-I Lin; Leen Vijgen; Maxwell D Cummings; Jimmy Lindberg; Jan Martin Berke; Pascale Dehertogh; Els Fransen; Annick Scholliers; Katrien Vermeiren; Tania Ivens; Pierre Raboisson; Michael Edlund; Susan Storm; Lotta Vrang; Herman de Kock; Gregory C Fanning; Kenneth A Simmen Journal: Antimicrob Agents Chemother Date: 2010-02-22 Impact factor: 5.191
Authors: Micaela B Reddy; Peter N Morcos; Sophie Le Pogam; Ying Ou; Karl Frank; Thierry Lave; Patrick Smith Journal: Antimicrob Agents Chemother Date: 2012-04-02 Impact factor: 5.191
Authors: Elodie Valade; Belén Valenzuela; Thomas N Kakuda; Christopher Westland; Matthew W McClure; Sivi Ouwerkerk-Mahadevan; Juan José Perez-Ruixo; Oliver Ackaert Journal: AAPS J Date: 2018-10-22 Impact factor: 4.009