title: Pharmacokinetics of the New Hepatitis C Virus NS3 Protease Inhibitor Narlaprevir following Single-Dose Use with or without Ritonavir in Patients with Liver Cirrhosis.
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 Cmaxand 2.45-fold (90% CI = 1.56 to 3.85) for AUC0-∞The geometric mean Cmaxand AUC0-∞in cirrhotic and healthy subjects were similar: 1,225.7 ng/ml for Cmaxand 15,213.1 ng · h/ml for AUC0-∞in cirrhotic subjects and 1,178.9 ng/ml for Cmaxand 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 Cmaxand 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.
authors.affiliation: Department of Gastroenterology and Hepatology, Institute of Nutrition, Moscow, Russian Federation.
authors.forename: V
authors.initials: V
authors.lastname: Isakov
authors.affiliation: Medical Department, R-Pharm, Moscow, Russian Federation.
authors.forename: D
authors.initials: D
authors.lastname: Koloda
authors.affiliation: Medical Department, R-Pharm, Moscow, Russian Federation.
authors.forename: N
authors.initials: N
authors.lastname: Tikhonova
authors.affiliation: Academician G. Chapidze Emergency Cardiology Center, Tbilisi, Georgia.
authors.forename: T
authors.initials: T
authors.lastname: Kikalishvili
authors.affiliation: Medical Department, R-Pharm, Moscow, Russian Federation krasavina@rpharm.ru.
authors.forename: E
authors.initials: E
authors.lastname: Krasavina
authors.affiliation: Cardiological Clinic GULI, Tbilisi, Georgia.
authors.forename: K
authors.initials: K
authors.lastname: Lekishvili
authors.affiliation: Ascent Clinical Research Solutions, Moscow, Russian Federation.
authors.forename: I
authors.initials: I
authors.lastname: Malaya
authors.affiliation: Quinta Analytica, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Ryska
authors.affiliation: Medical Department, R-Pharm, Moscow, Russian Federation.
authors.forename: M
authors.initials: M
authors.lastname: Samsonov
authors.affiliation: Federal Governmental Budget Healthcare Institution, Russian Academy of Science, Troitsk, Russian Federation.
authors.forename: V
authors.initials: V
authors.lastname: Tolkacheva
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003521:Cyclopropanes; D004151:Dipeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives; D008103:Liver Cirrhosis / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013450:Sulfones / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014508:Urea; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D004151:Dipeptides; D007930:Leucine; D011392:Proline; D019438:Ritonavir; D013450:Sulfones; D014508:Urea; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C552043:narlaprevir