64 Safety of the HCV Protease Inhibitor Tmc435350 in Healthy Volunteers and Safety and Activity in Chronic Hepatitis C Infected Individuals: A Phase I Study

Reesink, H. W.; Verloes, René; Farha, Khalid Abou; Vliet, André van; Weegink, Christine J.; Klooster, Gerben van ’t; Aharchi, Fatima; Mariën, Kris; Remoortere, P. Van; Kock, Herman de; Broeckaert, Fabrice; Fanning, Gregory; Meyvisch, Paul; Beirendonck, E. Van; Simmen, Kenneth

doi:10.1016/s0168-8278(08)60066-5

Cited by 16 publications

(8 citation statements)

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“…The reasons for this are not clear, and while it remains speculative as to whether the NS3/4A inhibitors have an added therapeutic value via an innate immunity mode of action, there is at least theoretical and in vitro experimental evidence to support this view (18). Our in vitro data are supported by in vivo data in healthy volunteers and patients (37,45) that exposure to TMC435350 is sufficient to achieve levels in which restoration of the innate immune system is possible, providing a potential advantage of TMC435350 over drugs with lower trough levels. Further studies to elucidate the biochemical interaction of TMC435350 with HCV protease and inhibition studies on other genotypes, as well as detailed in vitro resistance characterization, are ongoing.…”

Section: Discussionmentioning

confidence: 60%

In Vitro Activity and Preclinical Profile of TMC435350, a Potent Hepatitis C Virus Protease Inhibitor

Lin¹,

Lenz²,

Fanning³

et al. 2009

Antimicrob Agents Chemother

184

143

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The hepatitis C virus (HCV) NS3/4A serine protease has been explored as a target for the inhibition of viral replication in preclinical models and in HCV-infected patients. TMC435350 is a highly specific and potent inhibitor of NS3/4A protease selected from a series of novel macrocyclic inhibitors. In biochemical assays using NS3/4A proteases of genotypes 1a and 1b, inhibition constants of 0.5 and 0.4 nM, respectively, were determined. TMC435350 inhibited HCV replication in a cellular assay (subgenomic 1b replicon) with a half-maximal effective concentration (EC 50 ) of 8 nM and a selectivity index of 5,875. The compound was synergistic with alpha interferon and an NS5B inhibitor in the replicon model and additive with ribavirin. In rats, TMC435350 was extensively distributed to the liver and intestinal tract (tissue/plasma area under the concentration-time curve ratios of >35), and the absolute bioavailability was 44% after a single oral administration. Compound concentrations detected in both plasma and liver at 8 h postdosing were above the EC 99 value measured in the replicon. In conclusion, given the selective and potent in vitro anti-HCV activity, the potential for combination with other anti-HCV agents, and the favorable pharmacokinetic profile, TMC435350 has been selected for clinical development.

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Section: Discussionmentioning

confidence: 60%

In Vitro Activity and Preclinical Profile of TMC435350, a Potent Hepatitis C Virus Protease Inhibitor

Lin¹,

Lenz²,

Fanning³

et al. 2009

Antimicrob Agents Chemother

184

143

View full text Add to dashboard Cite

show abstract

“…32 TMC435350 is a potent PI that led to HCV RNA declines of 3.9 log 10 IU/mL at day 6 with pharmacokinetics suggesting feasibility of once-daily dosing. 33 …”

Section: Hcv Ns3-4a Protease Inhibitorsmentioning

confidence: 99%

Avoiding therapeutic pitfalls: The rational use of specifically targeted agents against hepatitis C infection

2008

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The development of specifically targeted antiviral agents against hepatitis C is a major therapeutic advance that promises to markedly improve treatment response rates in patients with chronic infection. However, rapid emergence of drug resistance has already been described, the consequences of which are not yet understood. Although there are important differences between hepatitis C (HCV) and human immunodeficiency virus (HIV) infection, the judicious use of candidate agents against HCV should be guided by principles that have been established in the HIV therapeutic arena. In this review, we attempt to draw useful parallels between the development of antiretroviral therapy for HIV and preliminary data on antiviral agents for hepatitis C virus infection. Applying concepts learned in HIV therapeutics will hopefully lead to a prudent and cautious path in HCV treatment paradigms, particularly with respect to drug resistance. (HEPATOLOGY 2008;48:1700-1712

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“…TMC435350 is a NS3/4A protease inhibitor that was evaluated in patients with chronic HCV genotype 1 infection who had failed prior interferon treatment [24]. TMC435350 showed a median decline of HCV RNA of 3.5 log 10 IU/mL after 3 days of treatment and 3.9 log 10 IU/ mL after 6 days.…”

Section: Other Protease Inhibitorsmentioning

confidence: 99%

Treatment of chronic hepatitis C: Anticipated impact of resistance in patients treated with protease inhibitors

Kronenberger

Zeuzem

2009

Curr Gastroenterol Rep

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A main target of specifically targeted antiviral therapy for hepatitis C (STAT-C) is the NS3-protease, which has key functions in the hepatitis C virus (HCV) replication cycle. HCV/NS3-protease inhibitors have shown high antiviral activity in vitro and in patients with chronic hepatitis C. Protease-resistant HCV variants occurred rapidly in patients receiving protease-inhibitor monotherapy. The development of resistance can be best explained by selection of preexisting resistant variants, which grow out under selective pressure. Numerous mutations associated with resistance were identified. Clinical trials showed that protease-resistant strains are sensitive to interferon and that a triple combination of protease inhibitors, peginterferon, and ribavirin may improve the sustained virologic response rate compared with standard peginterferon/ribavirin combination therapy. Overall, it can be anticipated that successful treatment with protease inhibitors will require either combination therapy with peginterferon/ribavirin or a combination of STAT-C compounds with distinct modes of action and resistance patterns.

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64 Safety of the HCV Protease Inhibitor Tmc435350 in Healthy Volunteers and Safety and Activity in Chronic Hepatitis C Infected Individuals: A Phase I Study

Cited by 16 publications

References 0 publications

In Vitro Activity and Preclinical Profile of TMC435350, a Potent Hepatitis C Virus Protease Inhibitor

In Vitro Activity and Preclinical Profile of TMC435350, a Potent Hepatitis C Virus Protease Inhibitor

Avoiding therapeutic pitfalls: The rational use of specifically targeted agents against hepatitis C infection

Treatment of chronic hepatitis C: Anticipated impact of resistance in patients treated with protease inhibitors

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