Pibrentasvir API Manufacturers

General Description:

Pibrentasvir, identified by CAS number 1353900-92-1, is a notable compound with significant therapeutic applications. Pibrentasvir is a direct acting antiviral agent and Hepatitis C virus (HCV) NS5A inhibitor that targets the the viral RNA replication and viron assembly. In combination with , pibrentastiv is a useful therapy for patients who experienced therapeutic failure from other NS5A inhibitors. In cell cultures, the emergence of amino acid substitutions at known NS5A inhibitor resistance-associated positions in HCV genotype 1a, 2a or 3a replicons led to reduced susceptibility and resistance to pibrentasvir . These resistance-associated amino acid substitutions included Q30D/deletion, Y93D/H/N or H58D +Y93H in genotype 1a replicons, F28S + M31I or P29S + K30G in genotype 2a replicons, and Y93H in genotype 3a replicons. Individual NS5A amino acid substitutions that reduced susceptibility to pibrentasvir include M28G or Q30D in a genotype 1a replicon and P32-deletion in a genotype 1b replicon . Pibrentasvir 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:

Pibrentasvir undergoes metabolic processing primarily in: Pibrentasvir is not metabolized . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Pibrentasvir 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 110ng/mL in non-cirrhotic HCV-infected subjects. Relative to fasting conditions, the consumption of meals increases the absorption of pibrentasvir by 40-53% . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Pibrentasvir is an important consideration for its dosing schedule: The elimination half life (t1/2) is approximately 13 hours . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Pibrentasvir exhibits a strong affinity for binding with plasma proteins: Pibrentasvir is >99.9% bound to human plasma proteins. The Blood-to-plasma ratio is approximately 0.62 . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Pibrentasvir from the body primarily occurs through: The predominant route of elimination of the drug is biliary-fecal, where 96.6% of administered drug is excreted in feces and 0% of the drug is excreted in the urine . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Pharmacodynamics:

Pibrentasvir exerts its therapeutic effects through: Pibrentasvir is a pan-genotypic . According to HCV replicon assays, pibrentasvir has EC50 values ranging from 0.08-4.6 nM agaisnt laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a, or EC50 values of 0.5-4.3 pM against laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4b, 4d, 5a, 6a, 6e and 6p . It is active against common resistance-conferring substitutions in HCV genotypes 1 to 6 that confers resistance and decreased therapeutic response from other NS5A inhibitors, inluding positions 24, 28, 30, 31, 58, 92, or 93 in NS5A . In a QT study, pibrentasvir 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:

Pibrentasvir functions by: NS5A is a phosphoprotein that plays an essential role in replication, assembly and maturation of infectious viral proteins. The basal phosphorylated form of NS5A, which is maintained by C-terminal serine cluster, is key in ensuring its interaction with the viral capsid protein, or the core protein. By blocking this interaction, pibrentasvir inhibits the assembly of proteins and production of mature HCV particles . NS5A also interacts with viral and cellular proteins to form the HCV replicase complex, and supports the RNA replication of HCV . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Pibrentasvir belongs to the class of organic compounds known as phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group, classified under the direct parent group Phenylpiperidines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Piperidines class, specifically within the Phenylpiperidines subclass.

Categories:

Pibrentasvir is categorized under the following therapeutic classes: Antiinfectives for Systemic Use, Antiviral Agents, Antivirals for Systemic Use, Antivirals for treatment of HCV infections, BCRP/ABCG2 Inhibitors, BCRP/ABCG2 Substrates, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 Enzyme Inhibitors, Direct Acting Antivirals, Hepatitis C Virus NS5A Inhibitor, Heterocyclic Compounds, Fused-Ring, OATP1B1/SLCO1B1 Inhibitors, OATP1B3 inhibitors, Organic Anion Transporting Polypeptide 1B1 Inhibitors, Organic Anion Transporting Polypeptide 1B3 Inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, 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 Pibrentasvir include:

• Water Solubility:<0.1 mg/mL