Abstract
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 (Cmax) and the area under the concentration-time curve from 0 to infinity (AUC0–∞) 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 Cmax and 2.45-fold (90% CI = 1.56 to 3.85) for AUC0–∞. The geometric mean Cmax and AUC0–∞ in cirrhotic and healthy subjects were similar: 1,225.7 ng/ml for Cmax and 15,213.1 ng · h/ml for AUC0–∞ in cirrhotic subjects and 1,178.9 ng/ml for Cmax and 14,257.2 ng · h/ml for AUC0–∞ in healthy volunteers. The corresponding geometric mean ratios were 1.04 (90% CI = 0.67 to 1.62) for Cmax and 1.07 (90% CI = 0.72 to 1.58) for AUC0–∞. 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.
Highlights
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
Phase II clinical trials have shown that the addition of 200 mg of NVR with RTV at 100 mg for 12 weeks to peginterferon and ribavirin significantly increases the rates of sustained virological response (SVR) up to 85% in treatment-naive noncirrhotic patients with chronic hepatitis C virus (HCV) genotype 1 infection [3]
Individually matched to cirrhotic patients based on gender, age, body mass index (BMI), and smoking status, were deemed healthy based on medical history, physical examination, laboratory tests, and 12-lead electrocardiograms and had negative test results for hepatitis B virus surface antigen and HCV antibodies
Summary
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. The geometric mean maximum concentration of a drug in serum (Cmax) and the area under the concentration-time curve from 0 to infinity (AUC0–ؕ) 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 Cmax and 2.45-fold (90% CI ؍1.56 to 3.85) for AUC0–ؕ. HCV-related morbidity and mortality rates are increasing both globally and in Eastern Europe [4, 5] due to a substantial number of patients with advanced liver disease and liver cirrhosis. Pharmacokinetics of New HCV NS3 Protease Inhibitor with RTV in patients with compensated liver cirrhosis and in matched healthy controls
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