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.T he introduction of direct-acting antiviral (DAA) drugs with activity against the hepatitis C virus (HCV) is expected to significantly reduce the growing impact of this global epidemic, providing better treatment options to many patients and reducing the economic burden of disease. To realize the full potential of these emerging therapies, it is important to have an understanding of those factors which directly impact the clinical efficacy of these drugs. One important factor is the relationship between pharmacokinetics and pharmacodynamics (PK/PD), which aims to provide the link between a dosage regimen and a clinical outcome. For antiviral activity, this link requires knowledge of the concentration of drug at the site of action and the susceptibility of the virus to the particular drug of interest. Understanding the PK/PD of a particular drug or drug class then allows for the optimization of dosing regimens in clinical practice, enhances the ability to select the most appropriate doses during the drug development process, and helps guide the design and selection of future drug candidates.The FDA recommends that in phase 1b studies in HCV patients, doses be selected so that the total plasma trough concentration (C min ) is higher than the protein-shifted 50% effective concentration (EC 50,PS ) by severalfold (12). Although longer monotherap...

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“…By extrapolation (Fig. 2C), we also determined the IIP 100 , defined as the IIP when D = 100 × IC 50 , to estimate the effects of high drug concentrations, because clinical doses can range between 10-and 100-fold above the IC 50 (19). We found that previous or current first-line drugs against HCV infection, such as IFN-α, TPV, SMV, and SOF, as well as CIs, can inhibit more than 99% of HCV replication in this concentration range (IIP 100 > 2).…”

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