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 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.

Current therapy for chronic hepatitis C: The role of direct-acting antivirals

“…Early clinical studies suggested that narlaprevir plus PegIFNa/RBV offered an SVR12 rate up to 59.3% (19/32) in GT1-infected patients (de Bruijne et al, 2010). After a single dose of 200 mg, narlaprevir exposures were higher in cirrhotic patients than in healthy patients (Isakov et al, 2016). A phase 3 trial of narlaprevir (ClinicalTrials, gov identifier: NCT00689390) was terminated due to post-marketing commitments.…”

“…AV4025 -As an active NS5A inhibitor, AV4025 containing 5- [4-(4-imidazol-4-yl-phenyl)-buta-1,3-diynyl]-1H-imidazole linkers offered potent antiviral activity (EC 50 ¼ 3.4 ± 0.2 pM for GT1b) and favorable pharmacokinetic features in rats and dogs (Ivachtchenko et al, 2014).…”

Evolution of efficacious pangenotypic hepatitis C virus therapies

“…It demonstrated a good safety profile in addition to being potent in its antiviral activity. In 2016, R‐pharm introduced narlaprevir in the Russian population as the first antiviral drug for the treatment of chronic hepatitis C infection (Figure ) …”

One‐Pot Synthesis of Cyclopropane‐Fused Cyclic Amidines: An Oxidative Carbanion Cyclization

“…Heterocyclic ring systems bearing a cyclopropane moiety occur in many biologically active natural products, including alkaloids, terpenes, pheromones, herbicides, and fatty acid metabolites . The 3‐azabicyclo[ n .1.0]alkane framework is present in several pharmaceuticals, such as the antibacterial agent trovafloxacin, the anti‐addiction agent amitifadine, the attention deficit hyperactivity disorder (ADHD) drug candidate centanafadine, the analgesic agent bicifadine, the antidepressant drug candidate GSK1360707, and narlaprevir, a protease‐inhibitor drug for the treatment of hepatitis C virus (HCV) infection (Figure ).As a result of their medicinal applications, several synthetic approaches have been reported for the construction of 3‐azabicyclo[ n .1.0]alkane derivatives…”

“…Moreover, 2‐substituted allyl amine derivatives 23 a and 23 b underwent smooth reactions to furnish cyclopropane‐fused bicyclic amidines 24 a and 24 b , respectively, with two contiguous quaternary centers (Table , entry 10). Similarly, 3,3‐disubstituted allyl amine 25 furnished the corresponding 3‐azabicyclo[3.1.0]hexane derivative 26 , a key structural subunit present in narlaprevir (Table , entry 11) . Conspicuously, tosyl azide analogues, such as mesyl azide, benzenesulfonyl azide, and diphenylphosphoryl azide, reacted readily to furnish the corresponding cyclic amidine derivatives 27 a, 27 b , and 27 c , respectively, in good yields (Table , entry 12).…”