Narlaprevir (
SCH 900518) is a potent inhibitor of the hepatitis C virus (HCV) nonstructural
protein 3
serine protease that is primarily metabolized by the
cytochrome P450-3A4 system. In order to explore the use of
ritonavir-based pharmacokinetic enhancement of an HCV
protease inhibitor, this study investigated the safety, tolerability, pharmacokinetics, and
antiviral activity of
narlaprevir (with or without
ritonavir) administered as monotherapy and as combination
therapy with pegylated interferon-α-2b (PEG-IFN-α-2b) to HCV genotype 1-infected patients. This was a randomized, placebo-controlled, two-period, blinded study in 40 HCV genotype 1-infected patients (naïve and treatment-experienced). In period 1,
narlaprevir was administered for 7 days as 800 mg three times daily without
ritonavir or 400 mg twice daily with 200 mg
ritonavir twice daily. In period 2, after a 4-week washout, the same dose and regimen of
narlaprevir was administered in combination with PEG-IFN-α-2b for 14 days. Upon completion of period 2, all patients initiated PEG-IFN-α-2b and
ribavirin treatment. A rapid and persistent decline in plasma HCV-
RNA was observed in both treatment-experienced and treatment-naïve patients during period 1, with a mean viral load decline of at least 4 log₁₀ in all treatment groups. A high percentage of both treatment-experienced (50%) and treatment-naïve (≥ 60%) patients had undetectable HCV-
RNA (< 25 IU/mL) after period 2. Standard of care resulted in sustained virological response (SVR) rates of 38% and 81% in treatment-experienced and treatment-naïve patients, respectively.
Narlaprevir (with or without
ritonavir) alone or in combination with PEG-IFN-α-2b was safe and well tolerated.
CONCLUSION: