Author:
Duan Jianmin,Bolger Gordon,Garneau Michel,Amad Ma'an,Batonga Joëlle,Montpetit Hélène,Otis François,Jutras Martin,Lapeyre Nicole,Rhéaume Manon,Kukolj George,White Peter W.,Bethell Richard C.,Cordingley Michael G.
Abstract
ABSTRACTPharmacokinetic-pharmacodynamic (PK-PD) data analyses from early hepatitis C virus (HCV) clinical trials failed to show a good correlation between the plasma inhibitory quotient (IQ) and antiviral activity of different classes of directly acting antiviral agents (DAAs). The present study explored whether use of the liver partition coefficient-corrected IQ (LCIQ) could improve the PK-PD relationship. Animal liver partition coefficients (Kpliver) were calculated from liver to plasma exposure ratios.In vitrohepatocyte partition coefficients (Kphep) were determined by the ratio of cellular to medium drug concentrations. Human Kpliverwas predicted using anin vitro-in vivoproportionality method: the species-averaged animal Kplivermultiplied by the ratio of human Kphepover those in animals. LCIQ was calculated using the IQ multiplied by the predicted human Kpliver. Our results demonstrated that thein vitro-in vivoproportionality approach provided the best human Kpliverprediction, with prediction errors of <45% for all 5 benchmark drugs evaluated (doxorubicin, verapamil, digoxin, quinidine, and imipramine). Plasma IQ values correlated poorly (r2of 0.48) with maximum viral load reduction and led to a corresponding 50% effective dose (ED50) IQ of 42, with a 95% confidence interval (CI) of 0.1 to 148534. In contrast, the LCIQ-maximum VLR relationship fit into a typical sigmoidal curve with anr2value of 0.95 and an ED50LCIQ of 121, with a 95% CI of 83 to 177. The present study provides a novel human Kpliverprediction model, and the LCIQ correlated well with the viral load reductions observed in short-term HCV monotherapy of different DAAs and provides a valuable tool to guide HCV drug discovery.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
20 articles.
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