The liver partition coefficient-corrected inhibitory quotient and the pharmacokinetic-pharmacodynamic relationship of directly acting anti-hepatitis C virus agents in humans

Abstract

Pharmacokinetic-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 vitro hepatocyte partition coefficients (Kphep) were determined by the ratio of cellular to medium drug concentrations. Human Kpliver was predicted using an in vitro-in vivo proportionality method: the species-averaged animal Kp liver multiplied by the ratio of human Kphep over those in animals. LCIQ was calculated using the IQ multiplied by the predicted human Kpliver. Our results demonstrated that the in vitro-in vivo proportionality approach provided the best human Kpliver prediction, with prediction errors of <45% for all 5 benchmark drugs evaluated (doxorubicin, verapamil, digoxin, quinidine, and imipramine). Plasma IQ values correlated poorly (r2 of 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 an r2 value of 0.95 and an ED50 LCIQ of 121, with a 95% CI of 83 to 177. The present study provides a novel human Kpliver prediction 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. Copyright © 2012, American Society for Microbiology. All Rights Reserved.