Rapid HCV-RNA Decline With Once Daily TMC435: A Phase I Study in Healthy Volunteers and Hepatitis C Patients

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

doi:10.1053/j.gastro.2009.10.033

Cited by 149 publications

(121 citation statements)

References 17 publications

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“…Decreased expression of several hepatic P450s and transporters is correlated with the progression of fibrosis (48). For several HCV compounds, significant differences in PK have been observed between healthy volunteers and HCV patients, e.g., for PI TMC435350 (60) and NNPolI IDX375 (9).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Predictors of Clinical Potency for Hepatitis C Virus Nonnucleoside Polymerase and Protease Inhibitors

Reddy

Morcos

Pogam

et al. 2012

Antimicrob Agents Chemother

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This analysis was conducted to determine whether the hepatitis C virus (HCV) viral kinetics (VK) model can predict viral load (VL) decreases for nonnucleoside polymerase inhibitors (NNPolIs) and protease inhibitors (PIs) after 3-day monotherapy studies of patients infected with genotype 1 chronic HCV. This analysis includes data for 8 NNPolIs and 14 PIs, including VL decreases from 3-day monotherapy, total plasma trough concentrations on day 3 (C min ), replicon data (50% effective concentration [EC 50 ] and protein-shifted EC 50 [EC 50,PS ]), and for PIs, liver-to-plasma ratios (LPRs) measured in vivo in preclinical species. VK model simulations suggested that achieving additional log 10 VL decreases greater than one required 10-fold increases in the C min . NNPolI and PI data further supported this result. The VK model was successfully used to predict VL decreases in 3-day monotherapy for NNPolIs based on the EC 50,PS and the day 3 C min . For PIs, however, predicting VL decreases using the same model and the EC 50,PS and day 3 C min was not successful; a model including LPR values and the EC 50 instead of the EC 50,PS provided a better prediction of VL decrease. These results are useful for designing phase 1 monotherapy studies for NNPolIs and PIs by clarifying factors driving VL decreases, such as the day 3 C min and the EC 50,PS for NNPolIs or the EC 50 and LPR for PIs. This work provides a framework for understanding the pharmacokinetic/pharmacodynamic relationship for other HCV drug classes. The availability of mechanistic data on processes driving the target concentration, such as liver uptake transporters, should help to improve the predictive power of the approach.T he introduction of direct-acting antiviral (DAA) drugs with activity against the hepatitis C virus (HCV) is expected to significantly reduce the growing impact of this global epidemic, providing better treatment options to many patients and reducing the economic burden of disease. To realize the full potential of these emerging therapies, it is important to have an understanding of those factors which directly impact the clinical efficacy of these drugs. One important factor is the relationship between pharmacokinetics and pharmacodynamics (PK/PD), which aims to provide the link between a dosage regimen and a clinical outcome. For antiviral activity, this link requires knowledge of the concentration of drug at the site of action and the susceptibility of the virus to the particular drug of interest. Understanding the PK/PD of a particular drug or drug class then allows for the optimization of dosing regimens in clinical practice, enhances the ability to select the most appropriate doses during the drug development process, and helps guide the design and selection of future drug candidates.The FDA recommends that in phase 1b studies in HCV patients, doses be selected so that the total plasma trough concentration (C min ) is higher than the protein-shifted 50% effective concentration (EC 50,PS ) by severalfold (12). Although longer monotherap...

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Predictors of Clinical Potency for Hepatitis C Virus Nonnucleoside Polymerase and Protease Inhibitors

Reddy

Morcos

Pogam

et al. 2012

Antimicrob Agents Chemother

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“…[4][5][6][7] However, combinations of potent direct-acting antiviral agents targeting different stages of the HCV life cycle offer the possibility of interferonfree treatment. The results of phase 1 and 2 studies involving patients with HCV genotype 1 infection have been encouraging and provide support for further development of combination therapies.…”

Section: Resultsmentioning

confidence: 99%

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Zeuzem¹,

Soriano²,

Asselah³

et al. 2013

N Engl J Med

211

173

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BACKGROUND: Interferon-free regimens would be a major advance in the treatment of patients with chronic hepatitis C virus (HCV) infection. METHODS: In this phase 2b, randomized, openlabel trial of faldaprevir (a protease inhibitor) and deleobuvir (a nonnucleoside polymerase inhibitor), we randomly assigned 362 previously untreated patients with HCV genotype 1 infection to one of five groups: faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, plus ribavirin, for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); or faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). The primary end point was a sustained virologic response 12 weeks after the completion of therapy. RESULTS: The primary end point was met in 59% of patients in the TID16W group, 59% of patients in the TID28W group, 52% of patients in the TID40W group, 69% of patients in the BID28W group, and 39% of patients in the TID28W-NR group. The sustained virologic response 12 weeks after the completion of therapy did not differ significantly according to treatment duration or dosage among ribavirin-containing regimens. This response was significantly higher with TID28W than with TID28W-NR (P=0.03). Rates of a sustained virologic response 12 weeks after the completion of therapy were 56 to 85% among patients with genotype 1b infection versus 11 to 47% among patients with genotype 1a infection and 58 to 84% among patients with IL28B CC versus 33 to 64% with non-CC genotypes. Rash, photosensitivity, nausea, vomiting, and diarrhea were the most common adverse events. CONCLUSIONS: The rate of a sustained virologic response 12 weeks after the completion of therapy was 52 to 69% among patients who received interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin. (Funded by Boehringer Ingelheim; SOUND-C2 ClinicalTrials.gov number, NCT01132313.).

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“…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 breakthrough (>1 log 10 IU/ml HCV RNA increase from nadir) was observed during treatment nor in the 3 d post-treatment; HCV RNA returned to pretreatment levels by Week 4 after treatment cessation (Reesink et al, 2010). Viral breakthrough was infrequent in a TMC435 phase IIa study named OPERA-1 .…”

Section: Tmc435 (Tmc435350)mentioning

confidence: 94%

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

Tong

Wang

2012

J. Zhejiang Univ. Sci. B

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Abstract:Infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide. However, no vaccine or immunoglobulin is currently available for the prevention of HCV infection. The standard of care (SOC) involving pegylated interferon-α (PEG-IFN α) plus ribavirin (RBV) for 48 weeks results in a sustained virologic response in less than 50% of patients with chronic hepatitis C genotype 1, the most prevalent type of HCV in North America and Europe. Recently, reliable in vitro culture systems have been developed for accelerating antiviral therapy research, and many new specifically targeted antiviral therapies for hepatitis C (STAT-C) and treatment strategies are being evaluated in clinical trials. These new antiviral agents are expected to improve present treatment significantly and may potentially shorten treatment duration. The aim of this review is to summarize the current developments in new anti-HCV drugs.

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Rapid HCV-RNA Decline With Once Daily TMC435: A Phase I Study in Healthy Volunteers and Hepatitis C Patients

Cited by 149 publications

References 17 publications

Pharmacokinetic/Pharmacodynamic Predictors of Clinical Potency for Hepatitis C Virus Nonnucleoside Polymerase and Protease Inhibitors

Pharmacokinetic/Pharmacodynamic Predictors of Clinical Potency for Hepatitis C Virus Nonnucleoside Polymerase and Protease Inhibitors

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

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