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General Description:

Asunaprevir, identified by CAS number 630420-16-5, is a notable compound with significant therapeutic applications. Asunaprevir, also named BMS-650032, is a potent hepatitis C virus (HCV) NS3 protease inhibitor. It has been shown to have a very high efficacy in dual-combination regimens with daclatasvir in patients chronically infected with HCV genotype 1b. It was developed by Bristol-Myers Squibb Canada and approved by Health Canada on April 22, 2016. The commercialization of asunaprevir was cancelled one year later on October 16, 2017.

Indications:

This drug is primarily indicated for: 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. 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%. The genotype 1 is the most common type of hepatitis C in the United States and the most difficult to treat. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Asunaprevir undergoes metabolic processing primarily in: Asunaprevir is metabolized by the liver. The metabolism is mainly marked by oxidative reactions mediated by the activity of CYP3A. Asunaprevir seems to weakly induce its own metabolism and from the circulating dose, just about 5% of the administered dose is formed by metabolites. 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Asunaprevir are crucial for its therapeutic efficacy: In preclinical studies, asunaprevir showed a high liver-to-plasma AUC ratio. It is rapidly absorbed within 30 minutes of administration. Clinical pharmacokinetic studies showed a T_max of 2-4 hours. The pharmacokinetic profile act in a dose-proportional manner and in a dose of 100 mg the steady-state C_max and AUC was 572 ng/ml and 1887 ng x h/mL. The absolute bioavailability is reported to be 9.3%. The absorption of asunaprevir is increased with food. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Asunaprevir is an important consideration for its dosing schedule: Clinical pharmacokinetic studies showed a mean terminal half-life of 15-20 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Asunaprevir exhibits a strong affinity for binding with plasma proteins: Protein binding of asunaprevir is very high and it can reach more than 99% of the administered dose independently of the dose. _In vitro_ studies with human Caco-2 cells indicated that asunaprevir is a substrate of P-gp, OATP1B1 and OATP2B1. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Asunaprevir from the body primarily occurs through: Asunaprevir is primarily eliminated via the feces. From the administered dose, 84% is excreted by feces mainly as metabolites and less than 1% of the dose is recovered as metabolites in the urine. The proportion of unchanged asunaprevir recovered in feces represents only 7.5% of the dose. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Asunaprevir is distributed throughout the body with a volume of distribution of: The registered volume of distribution at steady state is 194 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Asunaprevir is a critical factor in determining its safe and effective dosage: Clinical pharmacokinetic studies showed a mean oral clearance of 302-491 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Asunaprevir exerts its therapeutic effects through: Studies in vitro demonstrated a significant antiviral activity in HCV replicon cell systems with an EC50 of 4nm and 1nm against the HCV genotype 1a and 1b respectively. These studies showed a limited activity against the genotypes 2 and 3. This property makes asunaprevir a highly selective anti-HCV agent that is not effective against HCV closely related virus. Asunaprevir produce robust declines in HCV RNA levels in patients with HCV genotype 1 infection.In clinical studies, it has been shown that asunaprevir is well-tolerated and the mean maximum HCV RNA level reduction from baseline was of approximately 2.87 log10 IU/ml. Monotherapy clinical studies with asunaprevir showed a mean maximum decline of HCV RNA in the range of 0.28-2.87 log10 IU/ml when administered in increasing doses from 10-600 mg. When asunaprevir was used as a combination product, it was possible to obtain a sustained virological response (aviremia 24 weeks after completion of therapy) in 83-92% of the patients. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Asunaprevir functions by: Asunaprevir is a highly active HCV NS3 protease inhibitor. 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Asunaprevir belongs to the class of organic compounds known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds, classified under the direct parent group Oligopeptides. This compound is a part of the Organic compounds, falling under the Organic acids and derivatives superclass, and categorized within the Carboxylic acids and derivatives class, specifically within the Amino acids, peptides, and analogues subclass.

Categories:

Asunaprevir is categorized under the following therapeutic classes: Amides, Antiinfectives for Systemic Use, Antiviral Agents, Antivirals for Systemic Use, Antivirals for treatment of HCV infections, Cytochrome P-450 CYP2A6 Substrates, Cytochrome P-450 CYP2B6 Substrates, Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP2D6 Inhibitors, Cytochrome P-450 CYP2D6 Inhibitors (moderate), Cytochrome P-450 CYP2D6 Substrates, Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (weak), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Inducers, Cytochrome P-450 CYP3A5 Inducers (weak), Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Direct Acting Antivirals, Enzyme Inhibitors, HCV Protease Inhibitors, Heterocyclic Compounds, Fused-Ring, HIV Protease Inhibitors, OATP1B1/SLCO1B1 Inhibitors, OATP1B1/SLCO1B1 Substrates, OATP1B3 inhibitors, OATP2B1/SLCO2B1 substrates, Organic Anion Transporting Polypeptide 2B1 Inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, Protease Inhibitors, Sulfones, Sulfur Compounds. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Asunaprevir include:

• Water Solubility:<50 mg/L
• Melting Point: 145-155 ºC