Velpatasvir

Synthetic Routes and Reaction Conditions

The synthesis of velpatasvir involves multiple steps, starting from readily available starting materials. One of the key intermediates in the synthesis is a compound of formula 5, which is further converted to this compound or its pharmaceutically acceptable salts . The process involves the use of various reagents and solvents, including dimethylformamide (DMF) and cesium carbonate, under controlled reaction conditions .

Industrial Production Methods

Industrial production of this compound follows a similar synthetic route but is optimized for large-scale manufacturing. The process ensures high yield and purity of the final product. The production involves stringent quality control measures to ensure the consistency and safety of the medication .

Types of Reactions

Velpatasvir undergoes several types of chemical reactions, including:

Oxidation: this compound can be oxidized under specific conditions to form various oxidation products.

Reduction: Reduction reactions can be used to modify certain functional groups in this compound.

Substitution: this compound can undergo substitution reactions, where one functional group is replaced by another.

Common Reagents and Conditions

Common reagents used in these reactions include oxidizing agents like hydrogen peroxide, reducing agents like sodium borohydride, and various catalysts to facilitate substitution reactions. The reaction conditions, such as temperature and pH, are carefully controlled to achieve the desired products .

Major Products Formed

The major products formed from these reactions depend on the specific reaction conditions and reagents used. For example, oxidation of this compound can lead to the formation of hydroxylated derivatives, while reduction can yield deoxygenated products .

ASTRAL Studies

The ASTRAL studies (ASTRAL-1, ASTRAL-2, ASTRAL-3, ASTRAL-4, and ASTRAL-5) are pivotal Phase III clinical trials that evaluated the efficacy and safety of the sofosbuvir/velpatasvir combination. Key findings include:

• Overall SVR Rate : In a pooled analysis from ASTRAL-1, -2, and -3 involving 1,035 patients treated for 12 weeks, the overall SVR rate was 98% .
• Genotype Efficacy : The treatment demonstrated high efficacy across all genotypes (GT1-GT6), with minimal virological relapses noted .

SIMPLIFY Trial

The SIMPLIFY trial focused on individuals with recent injection drug use and chronic HCV infections. Participants received oral sofosbuvir and velpatasvir for 12 weeks. Results showed a significant proportion of patients achieving SVR12 (sustained virologic response at 12 weeks post-treatment) .

PANDAA-PED Study

A recent study, PANDAA-PED, assessed the efficacy of sofosbuvir/velpatasvir in children aged 6-18 years with chronic HCV infection. The study reported a 100% SVR12 rate among participants treated for 12 weeks . This suggests that this compound is effective not only in adults but also in pediatric populations.

Safety Profile

This compound has been associated with a favorable safety profile. Adverse events reported during clinical trials were mostly mild to moderate. For instance, in the PANDAA-PED study, adverse events were reported but did not lead to treatment discontinuation .

Ribavirin-Free Regimens

Research indicates that patients receiving ribavirin-free regimens containing sofosbuvir and this compound reported better patient-reported outcomes compared to those receiving ribavirin-containing regimens. This underscores the potential for improved quality of life during treatment .

Case Studies

Case Study 1: Treatment-naïve Patients

In a multicenter trial involving treatment-naïve patients with various HCV genotypes, the combination of sofosbuvir and this compound resulted in high SVR rates across different demographics and liver conditions .

Case Study 2: Co-infected Patients

Another significant application of this compound is its use in patients co-infected with HCV and HIV. Studies have shown that it is effective in achieving SVR among this population without compromising safety .

Velpatasvir exerts its effects by inhibiting the NS5A protein, which is crucial for the replication and assembly of HCV. By blocking this protein, this compound prevents the virus from replicating and assembling new viral particles. This inhibition leads to a reduction in viral load and helps in achieving a sustained virologic response (SVR) in patients .

Velpatasvir is compared with other NS5A inhibitors such as ledipasvir and daclatasvir. While all these compounds inhibit the NS5A protein, this compound has a higher barrier to resistance and is effective against all six major genotypes of HCV. This makes it a more potent and reliable option for treating chronic HCV infections .

List of Similar Compounds

• Ledipasvir
• Daclatasvir
• Ombitasvir
• Elbasvir

This compound’s unique ability to target all HCV genotypes and its high resistance barrier make it a valuable addition to the arsenal of antiviral medications .

Velpatasvir (VEL), an NS5A inhibitor, is a key component of antiviral therapies targeting Hepatitis C Virus (HCV). It is most commonly used in combination with sofosbuvir (SOF) in the fixed-dose combination tablet Epclusa. This article explores the biological activity of this compound, detailing its mechanism of action, efficacy, safety, pharmacokinetics, and real-world applications.

This compound acts by inhibiting the NS5A protein, which is crucial for HCV replication. This inhibition disrupts the viral life cycle, leading to a decrease in viral load and ultimately contributing to viral eradication. The compound demonstrates potent antiviral activity against all six major genotypes of HCV (GT1 to GT6), making it a pan-genotypic treatment option.

Efficacy Data

Clinical studies have shown that this compound, particularly when combined with Sofosbuvir, achieves high rates of sustained virologic response (SVR). The following table summarizes key findings from various studies:

The combination therapy has shown over 95% SVR across diverse patient populations, including those with advanced liver disease and prior treatment failures.

Safety Profile

This compound is generally well tolerated, with a safety profile comparable to placebo. Common adverse effects include fatigue, headache, and nausea. Serious adverse events were reported in approximately 19% of patients treated for chronic HCV infection, but these were not necessarily attributed to the drug itself .

Pharmacokinetics

This compound exhibits favorable pharmacokinetic properties:

• Absorption : Peak plasma concentrations occur approximately 3 hours post-dose.
• Metabolism : Over 98% of this compound remains unchanged in plasma after administration.
• Half-Life : The terminal half-life is around 15 hours, allowing for once-daily dosing.
• Bioavailability : High bioavailability ensures effective systemic exposure.

Case Studies and Real-World Evidence

Recent studies have provided insights into the real-world effectiveness of this compound. A multicenter cohort study involving patients re-treated with VOX/VEL/SOF showed an overall SVR rate of 95%, indicating that this compound remains effective even in challenging cases where previous treatments have failed .

In Rwanda, a prospective trial demonstrated that a 12-week regimen of SOF/VEL was safe and efficacious for treating chronic HCV genotype 4 infections, achieving an SVR rate of over 90% . These findings underscore the versatility and reliability of this compound in various clinical settings.

Basic Research Questions

Q. What is the mechanism of action of velpatasvir against HCV, and how is this validated experimentally?

this compound inhibits the HCV NS5A protein, disrupting viral replication and assembly. Experimental validation involves:

• Replicon assays : Measuring 50% effective concentration (EC50) values in genotype-specific HCV replicons to assess potency .
• Resistance profiling : Identifying NS5A mutations (e.g., Y93H in genotype 3a) through site-directed mutagenesis and phenotypic testing .
• Clinical correlation : Confirming antiviral activity via sustained virologic response (SVR) rates in phase 3 trials (e.g., 95–99% SVR across genotypes) .

Q. How are clinical trials designed to evaluate drug-drug interactions (DDIs) involving this compound?

DDI studies focus on cytochrome P450 (CYP) enzymes and transporters (e.g., P-glycoprotein). Key methodologies:

• Pharmacokinetic (PK) crossover studies : Comparing this compound exposure (AUC, Cmax) with/without co-administered drugs (e.g., proton pump inhibitors) .
• Retrospective analysis : Pooling data from phase 2/3 trials to assess SVR rates in patients on concomitant medications (e.g., PPIs), even with incomplete dosing details .

Q. What in vitro models are used to study this compound’s pan-genotypic efficacy?

• Genotype-specific replicons : Testing EC50 values across HCV genotypes 1–6 .
• Chimeric mouse models : Humanized-liver mice infected with different HCV genotypes to evaluate viral load reduction post-treatment .

Advanced Research Questions

Q. How do NS5A resistance-associated substitutions (RASs) impact this compound’s efficacy, and how are these studied?

• Phenotypic resistance assays : Introducing RASs (e.g., L31V + Y93H in genotype 1b) into replicons to quantify fold-changes in EC50. RAS combinations often reduce susceptibility >100-fold .
• Clinical resistance analysis : Sequencing HCV RNA from non-responders to correlate RAS presence with virologic failure .

Q. What analytical methods are used to resolve stability and degradation profiles of this compound in formulations?

• RP-HPLC with UV detection : Quantifying this compound and degradation products under stress conditions (acid/base, oxidation) .
• Forced degradation studies : Exposing this compound to heat/light and using stability-indicating methods (e.g., HPTLC) to validate robustness .

Q. How is population pharmacokinetic (PopPK) modeling applied to optimize this compound dosing in special populations?

• Covariate analysis : Identifying factors (e.g., cirrhosis, age) affecting this compound exposure using nonlinear mixed-effects modeling (NONMEM). PopPK data show no clinically relevant exposure changes in hepatic impairment .
• Dose adjustment simulations : Predicting AUC changes in subpopulations (e.g., elderly patients) to guide dosing without compromising SVR .

Q. What strategies address virologic relapse in patients with prior DAA failure receiving this compound-based retreatment?

• Triple therapy : Combining sofosbuvir/velpatasvir with voxilaprevir (NS3/4A protease inhibitor) for 12 weeks, achieving 96% SVR in NS5A inhibitor-experienced patients .
• Ribavirin add-on : Extending treatment to 24 weeks with ribavirin, particularly effective in genotype 3 (78% SVR) .

Q. Methodological Contradictions & Resolutions

Q. How are contradictions between computational predictions and in vivo efficacy resolved?

Example: Initial in silico studies suggested this compound’s potential against SARS-CoV-2 3CL protease. Resolution steps:

• Experimental validation : Testing antiviral activity in cell-based assays (e.g., Vero E6 cells) .
• Clinical correlation : Prioritizing HCV-focused studies unless virologic evidence supports repurposing .

Q. Why do real-world SVR rates sometimes diverge from clinical trial data?

• Heterogeneity in RWD : Confounding factors (e.g., undocumented PPIs, adherence issues) necessitate multivariate regression to isolate this compound’s effect .
• Retrospective vs. prospective designs : RCTs control variables (e.g., PPI dosing), while RWD requires propensity score matching to reduce bias .

Q. Formulation & Bioavailability Optimization

Q. How is this compound’s bioavailability enhanced in fixed-dose combinations (FDCs)?

• pH modulation : Co-formulating with sofosbuvir in tablets optimized for gastric dissolution, mitigating PPI-induced pH elevation .
• Excipient screening : Using surfactants (e.g., sodium lauryl sulfate) to improve solubility, validated via dissolution testing .