Source Hoffmann-La Roche Inc., Nutley, NJ.
This analysis was conducted to determine whether the HCV viral kinetics (VK) model can predict viral load (VL) decreases for non-nucleoside polymerase inhibitors (NNPolIs) and protease inhibitors (PIs) after three-day monotherapy studies of patients infected with genotype 1 chronic hepatitis C virus (HCV). This analysis includes data for 8 NNPolIs and 14 PIs: VL decreases from three-day monotherapy, total plasma trough concentrations on Day 3, replicon data (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 log(10) VL decreases greater than one required 10-fold increases in Cmin. NNPolI and PI data further supported this result. The VK model was successfully used to predict VL decreases in three-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 PK/PD for other HCV drug classes. 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.