Singapore Drugs Database

Indication

Asunaprevir is indicated in combination with other agents for the treatment of chronic hepatitis C in adult patients with hepatitis C virus genotypes 1 or 4 and compensated liver cirrhosis.[L2278] Hepatitis C is a liver disease caused by the hepatitis C virus. The chronic state of this condition accounts for 60-80% of the cases from which the risk of cirrhosis of the liver within 20 years is of around 15-30%.[L2281] The genotype 1 is the most common type of hepatitis C in the United States and the most difficult to treat.[L2282]

Mechanism of Action

Asunaprevir is a highly active HCV NS3 protease inhibitor.[A32527] The genome of HCV has a positive polarity which allows it to be translated into a protein in the host cell without further transformation steps. However, the resultant protein needs to be divided by the enzyme NS3 protease into single proteins in order to be able to exert its enzymatic activity or structural role. Therefore, due to NS3 vital importance for viral replication, the inhibiting action of asunaprevir causes a robust antiviral activity.[A18434]

Pharmacokinetics

Absorption

In preclinical studies, asunaprevir showed a high liver-to-plasma AUC ratio. It is rapidly absorbed within 30 minutes of administration.[L2278] Clinical pharmacokinetic studies showed a tmax of 2-4 hours.[A18434] The pharmacokinetic profile act in a dose-proportional manner and in a dose of 100 mg the steady-state Cmax and AUC was 572 ng/ml and 1887 ng.h/ml. The absolute bioavailability is reported to be 9.3%. The absorption of asunaprevir is increased if it is accompanied by a high-fat diet.[L2287]

Distribution

The registered volume of distribution at steady state is 194 L.[L2287]

Metabolism

Asunaprevir is metabolized by the liver.[A18434] The metabolism is mainly marked by oxidative reactions mediated by the activity of CYP3A.[L2287] Asunaprevir seems to weakly induce its own metabolism and from the circulating dose, just about 5% of the administered dose is formed by metabolites.[L2278] The metabolites of asunaprevir are formed after mono- and bis-oxidation, N-dealkylation, loss of isoquinoline ring and O-demethylation. All the metabolic reactions form about 15 metabolites and studies have reported that the main metabolic activity is performed by CYP3A4 and CYP3A5 with some minor activity from CYP2A6, CYP2B6, CYP2C9, CYP2C19 and CYP2D6.[L2293]

Elimination

Clearance

Clinical pharmacokinetic studies showed a mean oral clearance of 302-491 L/h.[A18434]

Toxicity

Toxicity studies showed no carcinogenic nor genotoxic potential related to asunaprevir. In case of overdose, clinical studies reported no unexpected adverse events.[L2287]Asunaprevir had no effects on fertility in preclinical studies. It has been shown that asunaprevir gets localized in GI tract and liver and thus, increased in hepatic transaminases were observed as well as changes in iron metabolism, decreased in serum proteins. These effects are not progressive and asunaprevir was generally well tolerated.[L2278]

Active Ingredient/Synonyms

Asunaprevir | Asunaprevir |