Abstract
The relationship of inhibitory quotient (IQ) with the virologic response to specific inhibitors of human hepatitis C virus (HCV) and the best method to correct for serum protein binding in calculating IQ have not been addressed. A common method is to determine a fold shift by comparing the EC(50) values determined in cell culture in the absence and presence of human serum (fold shift in EC(50) ), but this method has a number of disadvantages. In the present study, the fold shifts in drug concentrations between 100% human plasma (HP) and cell culture medium (CCM) were directly measured using a modified comparative equilibrium dialysis (CED) assay for three HCV protease inhibitors (PIs) and for a novel HCV inhibitor GS-9132. The fold shift values in drug concentration between the HP and CCM (CED ratio) were ∼1 for SCH-503034, VX-950 and GS-9132 and 13 for BILN-2061. These values were ∼3-10-fold lower than the fold shift values calculated from the EC(50) assay for all inhibitors except BILN-2061. Using the CED values, a consistent pharmacokinetic and pharmacodynamic relationship was observed for the four HCV inhibitors analysed. Specifically, an approximate 1 log(10) reduction in HCV RNA was achieved with an IQ close to 1, while 2-3 and greater log(10) reductions in HCV RNA were achieved with IQ values of 3-5 and greater, respectively. Thus, use of CED to define IQ provides a predictive and quantitative approach for the assessment of the in vivo potency of HCV PIs and GS-9132. This method provides a framework for the evaluation of other classes of drugs that are bound by serum proteins but require the presence of serum for in vitro evaluation.
© 2010 Blackwell Publishing Ltd.
MeSH terms
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology*
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Antiviral Agents / therapeutic use
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Blood Proteins / metabolism
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Carbamates / pharmacokinetics
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Carbamates / pharmacology
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Carbamates / therapeutic use
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Cell Line
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Comparative Effectiveness Research
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Dialysis / methods
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Hepacivirus / drug effects*
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Hepacivirus / genetics
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Hepacivirus / pathogenicity
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Hepatitis C / drug therapy*
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Hepatitis C / virology
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Humans
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Inhibitory Concentration 50
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Macrocyclic Compounds / pharmacokinetics
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Macrocyclic Compounds / pharmacology
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Macrocyclic Compounds / therapeutic use
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Membranes, Artificial
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Oligopeptides / pharmacokinetics
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Oligopeptides / pharmacology
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Oligopeptides / therapeutic use
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Phenylthiourea / analogs & derivatives
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Phenylthiourea / pharmacokinetics
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Phenylthiourea / pharmacology
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Phenylthiourea / therapeutic use
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Plasma / virology
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Proline / analogs & derivatives
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Proline / pharmacokinetics
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Proline / pharmacology
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Proline / therapeutic use
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology*
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Protease Inhibitors / therapeutic use
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Protein Binding / drug effects
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Quinolines / pharmacokinetics
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Quinolines / pharmacology
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Quinolines / therapeutic use
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RNA, Viral / blood
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology
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Thiazoles / therapeutic use
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Viral Load / drug effects*
Substances
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1-(4-pentyloxy-3-trifluoromethylphenyl)-3-(pyridine-3-carbonyl)thiourea
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Antiviral Agents
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BILN 2061
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Blood Proteins
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Carbamates
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Macrocyclic Compounds
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Membranes, Artificial
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Oligopeptides
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Protease Inhibitors
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Quinolines
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RNA, Viral
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Thiazoles
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telaprevir
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Phenylthiourea
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N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide
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Proline