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Glecaprevir API Manufacturers & Suppliers

General Description:

Glecaprevir, identified by CAS number 1365970-03-1, is a notable compound with significant therapeutic applications. Glecaprevir is a direct acting antiviral agent and Hepatitis C virus (HCV) NS3/4A protease inhibitor that targets the the viral RNA replication. In combination with , glecaprevir is a useful therapy for patients who experienced therapeutic failure from other NS3/4A protease inhibitors. It demonstrates a high genetic barrier against resistance mutations of the virus. In cell cultures, the emergence of amino acid substitutions at NS3 resistance-associated positions A156 or D/Q168 in HCV genotype 1a, 2a or 3a replicons led to reduced susceptibility to glecaprevir . The combinations of amino acid substitutions at NS3 position Y65H and D/Q168 also results in greater reductions in glecaprevir susceptibility, and NS3 Q80R in genotype 3a patients also leads to glecaprevir resistance . Glecaprevir is available as an oral combination therapy with under the brand name Mavyret. This fixed-dose combination therapy was FDA-approved in August 2017 to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis, including patients with moderate to severe kidney disease and those who are on dialysis . Mavyret is also indicated for HCV genotype 1-infected patients who have been previously treated with regimens either containing an NS5A inhibitor or an NS3/4A protease inhibitor, but not both . Hepatitis C viral infection often leads to decreased liver function and subsequent liver failure, causing a significantly negative impact on the patients' quality of life. The ultimate goal of the combination treatment is to achieve sustained virologic response (SVR) and cure the patients from the infection. In clinical trials, this combination therapy achieved SVR12 rate, or undetectable Hepatitis C for twelve or more weeks after the end of treatment, of ≥93% across genotypes 1a, 2a, 3a, 4, 5 and 6 .

Indications:

This drug is primarily indicated for: Indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A). MAVYRET is also indicated for the treatment of adult patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Glecaprevir undergoes metabolic processing primarily in: Glecaprevir undergoes limited secondary metabolism in vitro, predominantly by CYP3A . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Glecaprevir are crucial for its therapeutic efficacy: In healthy subjects, the time it takes to reach the peak plasma concentration (Tmax) is approximately 5 hours. The mean peak plasma concentration (Cmax) is 597ng/mL in non-cirrhotic HCV-infected subjects. Relative to fasting conditions, the consumption of meals increases the absorption of glecaprevir by 83-163% . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Glecaprevir is an important consideration for its dosing schedule: The elimination half life (t1/2) is approximately 6 hours . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Glecaprevir exhibits a strong affinity for binding with plasma proteins: Pibrentasvir is 97.5% bound to human plasma proteins. The Blood-to-plasma ratio is approximately 0.57 . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Glecaprevir from the body primarily occurs through: The predominant route of elimination of the drug is biliary-fecal, where 92.1% of administered drug is excreted in feces and 0.7% of the drug is excreted in the urine . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Pharmacodynamics:

Glecaprevir exerts its therapeutic effects through: In a biochemical assay studying clinical isolates of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a, glecaprevir displayed IC50 values ranging from 3.5 to 11.3 nM that resulted in inhibition of the proteolytic activity of recombinant NS3/4A enzymes. In HCV replicon assays, glecaprevir had median EC50 values of 0.08-4.6 nM against laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a . In a QT study, glecaprevir is not shown to prolong the QTc interval. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Glecaprevir functions by: Glecaprevir is an inhibitor of the HCV NS3/4A protease, which is a viral enzyme necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins . These multifunctional proteins, including NS3, are essential for viral replication. The N-terminal of NS3 protein confers serine protease activity, whileThe C-terminus of NS3 encodes a DExH/D-box RNA helicase which hydyolyzes NTP as an energy source to unwind double-stranded RNA in a 3′ to 5′ direction during replication of viral genomic RNA . NS4A is a cofactor for NS3 that directs the localization of NS3 and modulates its enzymatic activities . Glecaprevir disrupts the intracellular processes of the viral life cycle through inhibiting the NS3/4A protease activity of cleaving downstream junctions of HCV polypeptide and proteolytic processing of mature structural proteins . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Glecaprevir belongs to the class of organic compounds known as cyclic peptides. These are compounds containing a cyclic moiety bearing a peptide backbone, classified under the direct parent group Cyclic peptides. 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:

Glecaprevir is categorized under the following therapeutic classes: Acids, Acyclic, Amides, Amino Acids, Amino Acids, Branched-Chain, Amino Acids, Cyclic, Amino Acids, Essential, Amino Acids, Peptides, and Proteins, Aminobutyrates, Antiinfectives for Systemic Use, Antiviral Agents, Antivirals for Systemic Use, Antivirals for treatment of HCV infections, BCRP/ABCG2 Inhibitors, BCRP/ABCG2 Substrates, Butyrates, Cycloparaffins, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (weak), Cytochrome P-450 Enzyme Inhibitors, Direct Acting Antivirals, HCV NS3/4A Protease Inhibitors, Heterocyclic Compounds, Fused-Ring, Imino Acids, Isobutyrates, Lactams, NS3/4A Protease Inhibitors, OATP1B1/SLCO1B1 Inhibitors, OATP1B1/SLCO1B1 Substrates, OATP1B3 inhibitors, OATP1B3 substrates, Organic Anion Transporting Polypeptide 1B1 Inhibitors, Organic Anion Transporting Polypeptide 1B3 Inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, Sulfones, Sulfur Compounds, Treatments for Hepatitis C, UGT1A1 Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Glecaprevir include:

• Water Solubility:<0.1 to 0.3 mg/mL