Pharmacokinetic/Pharmacodynamic predictors of clinical potency for hepatitis C virus nonnucleoside polymerase and protease inhibitors

Abstract

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 (C(min)), replicon data (50% effective concentration [EC(50)] and protein-shifted EC(50) [EC(50,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 the C(min). 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 EC(50,PS) and the day 3 C(min). For PIs, however, predicting VL decreases using the same model and the EC(50,PS) and day 3 C(min) was not successful; a model including LPR values and the EC(50) instead of the EC(50,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 C(min) and the EC(50,PS) for NNPolIs or the EC(50) 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.

Fig 1

Simulated VL decrease from baseline as a function of time in monotherapy of patients infected with HCV GT-1 for different levels of inhibition.

Fig 2

Predicted (line) and observed (symbols) VL decrease from baseline on day 3 of NNPolI monotherapy (log₁₀ IU/ml) as a function of C_min/EC_50,PS.

Fig 3

Predicted (curve) and observed (symbols) VL decrease from baseline on day 3 of PI monotherapy (log₁₀ IU/ml) as a function of (a) C_min/EC_50,PS, (b) C_min/EC₅₀, (c) C_min × LPR/EC_50,PS, and (d) C_min × LPR/EC₅₀. ABT-450 and two of the four narlaprevir doses were coadministered with ritonavir.