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

• Published in: Antimicrobial Agents and Chemotherapy Vol. 56; no. 6; pp. 3144 - 3156
• Main Authors: Reddy, Micaela B, Morcos, Peter N, Le Pogam, Sophie, Ou, Ying, Frank, Karl, Lave, Thierry, Smith, Patrick
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.06.2012
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral Agents; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; antiviral properties; Biological and medical sciences; Data processing; drug therapy; Drugs; Experimental Therapeutics; genotype; Genotypes; Hepacivirus; Hepacivirus - drug effects; Hepatitis C virus; Human viral diseases; Humans; Infectious diseases; Kinetics; Liver; Medical sciences; Models, Theoretical; patients; Pharmacodynamics; Pharmacokinetics; Pharmacology. Drug treatments; prediction; Protease Inhibitors; Protease Inhibitors - pharmacokinetics; Protease Inhibitors - pharmacology; Proteinase inhibitors; replicon; simulation models; transporters; Viral diseases; Viral hepatitis; viral load; Pharmacodynamics; Non nucleoside compound; Hepatic disease; Biological activity; Infection; Virus; Viral disease; Digestive diseases; Antiviral; Flaviviridae; Predictive factor; Pharmacokinetics; Hepatitis C virus; Hepacivirus; Protease inhibitor; Viral hepatitis C; DNA polymerase inhibitor
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.06283-11

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 (Cmin), replicon data (50% effective concentration [EC50] and protein-shifted EC50 [EC50,PS]), and for PIs, liver-to-plasma ratios (LPRs) measured in vivo in preclinical species. VK model simulations suggested that achieving additional log10 VL decreases greater than one required 10-fold increases in the Cmin. 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 EC50,PS and the day 3 Cmin. For PIs, however, predicting VL decreases using the same model and the EC50,PS and day 3 Cmin was not successful; a model including LPR values and the EC50 instead of the EC50,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 Cmin and the EC50,PS for NNPolIs or the EC50 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.