Pharmacokinetics of the New Hepatitis C Virus NS3 Protease Inhibitor Narlaprevir following Single-Dose Use with or without Ritonavir in Patients with Liver Cirrhosis

In this study we sought to evaluate narlaprevir (NVR) pharmacokinetics (PK) after a single dose with or without ritonavir (RTV) in cirrhotic versus healthy subjects. NVR at 200 mg was administered to 8 healthy and 8 cirrhotic subjects, and NVR at 100 mg with RTV at 100 mg was administered to 8 healthy and 8 cirrhotic subjects. PK analysis was performed. The geometric mean maximum concentration of a drug in serum (C(max)) and the area under the concentration-time curve from 0 to infinity (AUC(0–∞)) were 563.1 ng/ml and 4,701.8 ng · h/ml in cirrhotic patients versus 364.8 ng/ml and 1,917.1 ng · h/ml in healthy volunteers, respectively. The geometric mean ratios of the PK parameters of cirrhotic subjects to healthy volunteers were 1.54-fold (90% confidence interval [CI] = 1.05 to 2.27) for C(max) and 2.45-fold (90% CI = 1.56 to 3.85) for AUC(0–∞). The geometric mean C(max) and AUC(0–∞) in cirrhotic and healthy subjects were similar: 1,225.7 ng/ml for C(max) and 15,213.1 ng · h/ml for AUC(0–∞) in cirrhotic subjects and 1,178.9 ng/ml for C(max) and 14,257.2 ng · h/ml for AUC(0–∞) in healthy volunteers. The corresponding geometric mean ratios were 1.04 (90% CI = 0.67 to 1.62) for C(max) and 1.07 (90% CI = 0.72 to 1.58) for AUC(0–∞). Higher exposures in cirrhotic subjects were safe and well tolerated. We found that NVR exposures after a 200-mg single dose were higher in cirrhotic subjects than in healthy subjects and that a 100-mg single dose of NVR boosted with RTV at 100 mg resulted in no significant PK differences between cirrhotic and healthy subjects.