During narlaprevir dosing, there were no treatment discontinuations and no serious AEs. The most frequently reported AEs were gastrointestinal symptoms and influenza-like illness. Addition of PEG-IFN-α-2b to the treatment regimen increased the frequency of AEs, however, these AEs (flu-like symptoms) were consistent with those expected for pegylated

IFN. Combination with ritonavir did selleck screening library not significantly affect the AE profile. Most AEs reported in patients receiving narlaprevir were mild or moderate in severity. None of these moderate events was considered to be related to the study drug. Consistent with the results in healthy volunteers, narlaprevir appeared to be safe and well tolerated in all patients. The secondary objectives were to investigate the antiviral activity and pharmacokinetic profile of narlaprevir. Narlaprevir demonstrated a profound antiviral activity in both treatment-naïve and treatment-experienced patients. A rapid and persistent mean HCV-RNA decline of at least 4 log10 IU/mL was achieved in all patients whether narlaprevir was administered for 7 days alone or with ritonavir. HCV-RNA levels returned to baseline at the end of a 4-week washout period. During 14 days of treatment

with narlaprevir with or without ritonavir in combination with PEG-IFN-α-2b, plasma HCV-RNA levels declined in two phases: a rapid decline within the first day followed by a more gradual PLX3397 order viral decline thereafter. Four patients who received narlaprevir achieved undetectable HCV-RNA (<15 IU/mL) after 14 days. Follow-up treatment with PEG-IFN-α-2b and RBV resulted in high SVR rates of 81% (13/16) in treatment-naïve patients and 38% (6/16) in treatment-experienced patients treated with narlaprevir (with or without ritonavir). A rapid viral response was a strong positive predictor for SVR in treatment-naïve (9/9) and treatment-experienced patients (6/7).

These results demonstrate that the rapid and profound decline in HCV-RNA that was observed after a short initial period (14 days) of narlaprevir dosing could result in an increased RVR rate and subsequently an increased SVR rate in both treatment-naïve Palmatine and treatment-experienced patients compared with regular SOC.4, 5, 20 This finding suggests that SVR rates may be further enhanced when the dosing period of narlaprevir is extended to a 12-week regimen, which is currently being assessed in a phase 2a trial.21 The pharmacokinetic objective of this study was to generate a mean Cmin at least five- to 10-fold above the replicon assay EC90 value of 40 nM (≈28 ng/mL). Analysis of the pharmacokinetic profile of narlaprevir monotherapy revealed plasma concentrations at least six times the EC90 at trough in all treatment groups after a 7-day dosing period. A quartile distribution of median Cmin of 170, 296, 1,150, and 1,725 ng/mL represented a median Cmin six- to 62-fold higher than the EC90 for narlaprevir.