Ledipasvir

Synthetic Routes and Reaction Conditions

The synthesis of Ledipasvir involves multiple steps, including the preparation of key intermediates. One method involves the preparation of a high-purity intermediate, (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid, through enzymatic hydrolysis . Another method involves late-stage cyclopropanation and fluorination processes, which provide a novel and efficient route for the preparation of this compound with a total yield of 20% over eight linear steps .

Industrial Production Methods

Industrial production of this compound focuses on optimizing yield, purity, and cost-effectiveness. The process typically involves the use of high-purity intermediates and environmentally friendly reaction conditions. The methods are designed to be scalable for large-scale production, ensuring high selectivity and reduced production costs .

Types of Reactions

Ledipasvir undergoes various chemical reactions, including:

Reduction: Reduction reactions are less common for this compound.

Substitution: Substitution reactions, particularly involving halogen atoms, are more relevant in the synthesis of this compound

Common Reagents and Conditions

Common reagents used in the synthesis and reactions of this compound include acetonitrile, acetic acid, and isopropyl ether. Reaction conditions often involve elevated temperatures and controlled environments to ensure high yield and purity .

Major Products Formed

The major product formed from the reactions involving this compound is the final active pharmaceutical ingredient used in the treatment of hepatitis C. Other intermediates and by-products are typically removed through purification processes .

Treatment of Hepatitis C

Ledipasvir is approved for use in combination with sofosbuvir in various treatment regimens:

• 8-week regimen : For treatment-naive patients without cirrhosis and low baseline HCV RNA levels (<6 million IU/mL).
• 12-week regimen : For a broader range of patients, including those with cirrhosis or prior treatment experience.

Efficacy Data:

• In clinical trials, sustained virologic response (SVR) rates have been reported as high as 95%-100% across different populations and treatment durations. For instance, a study involving 2,099 participants showed SVR12 rates of 96% for the 8-week regimen and 97% for the 12-week regimen .

Real-World Effectiveness

Real-world studies have corroborated clinical trial findings, demonstrating high SVR rates in diverse patient populations:

• A multicenter observational study reported SVR12 rates of 96% among patients treated with this compound-sofosbuvir for 8 weeks .
• Factors influencing treatment outcomes included liver function indicators such as albumin levels and bilirubin levels .

Safety Profile

The safety profile of this compound has been assessed in numerous studies. Common adverse effects include:

• Headache
• Fatigue
• Nausea

Serious adverse events are rare but can occur, particularly when ribavirin is included in the treatment regimen .

Comparative Efficacy

The combination therapy of this compound and sofosbuvir has been compared to other antiviral treatments. The following table summarizes key findings from various studies:

Case Studies

Several case studies highlight the effectiveness of this compound in diverse settings:

• Egyptian Cohort Study : This study enrolled 255 patients with HCV genotype 4 and demonstrated high SVR rates (95% for the 8-week regimen and 98% for the 12-week regimen), emphasizing its efficacy even among previously treated patients .
• HCV-TARGET Study : An extensive analysis involving over 2,000 participants showed that higher baseline albumin and lower bilirubin levels were associated with better treatment outcomes .

Ledipasvir inhibits the hepatitis C virus non-structural protein 5A (NS5A), which is crucial for viral RNA replication and assembly of HCV virions. By preventing the hyperphosphorylation of NS5A, this compound disrupts the production of viral proteins, thereby inhibiting viral replication and assembly .

Similar Compounds

Sofosbuvir: Another direct-acting antiviral used in combination with Ledipasvir. It inhibits the NS5B polymerase of HCV.

Daclatasvir: An NS5A inhibitor similar to this compound but with different pharmacokinetic properties.

Ombitasvir: Another NS5A inhibitor used in combination with other antiviral agents for HCV treatment

Uniqueness of this compound

This compound is unique due to its high potency against multiple HCV genotypes and its ability to achieve sustained virologic response (SVR) rates of over 95% when used in combination with sofosbuvir. Its long half-life and minimal side effects make it a preferred choice for HCV treatment .

Ledipasvir is a potent antiviral agent used primarily in the treatment of hepatitis C virus (HCV) infections. It functions as an NS5A inhibitor, targeting the NS5A protein crucial for HCV replication. This article provides a comprehensive overview of the biological activity of this compound, including its pharmacological properties, efficacy in clinical studies, and safety profile.

This compound inhibits HCV replication by binding to the NS5A protein, which is essential for viral RNA replication and assembly. Although the exact biochemical mechanism remains unconfirmed due to the lack of known enzymatic functions of NS5A, studies indicate that this compound effectively disrupts HCV lifecycle processes.

• In vitro Activity : this compound exhibits varying inhibitory concentrations (EC50) against different HCV genotypes:
  • Genotype 1a: 0.031 nM
  • Genotype 1b: 0.004 nM
  • Genotype 2a: 10.8 nM
  • Genotype 3: 10.1 nM
  • Genotype 4a: 0.045 nM .

Pharmacokinetics

This compound is characterized by high plasma protein binding (>99.8%) and demonstrates a wide volume of distribution. Following administration, it shows minimal metabolism with over 98% of systemic exposure attributed to the parent compound. The pharmacokinetic profile indicates a long mean residence time, supporting its efficacy in sustained viral response (SVR) outcomes .

Efficacy in Clinical Trials

Numerous clinical trials have evaluated the efficacy of this compound, often in combination with sofosbuvir (LDV/SOF). The following table summarizes key findings from prominent studies:

These results indicate that this compound combined with sofosbuvir is highly effective across various patient populations, including those with prior treatment failures and different HCV genotypes .

Safety Profile

The safety profile of this compound has been assessed in various studies, revealing that it is generally well tolerated. Common adverse events include headache and fatigue, particularly in patients receiving ribavirin alongside this compound . Serious adverse events are rare, making it a favorable option for many patients.

Case Studies

• Case Study: Treatment-Naïve Patients
  In a multicenter trial involving treatment-naïve patients with HCV genotype 4, SVR12 rates reached up to 98% after a 12-week regimen of LDV/SOF, demonstrating high effectiveness even in populations previously underrepresented in clinical trials .
• Case Study: Patients with HIV Co-Infection
  A study focusing on men with HIV co-infection who received an eight-week course of LDV/SOF achieved a remarkable SVR rate of 100%, highlighting the compound's efficacy even in complex patient populations .

Q. Basic: What are the standard analytical methods for quantifying Ledipasvir in pharmacokinetic studies?

Q: What validated chromatographic techniques are used to quantify this compound in plasma or formulations, and how are linearity and accuracy ensured? A: Reverse-phase high-performance liquid chromatography (RP-HPLC) is widely employed, with calibration curves established using absorbance spectra (200–400 nm). Linear ranges for this compound typically span 5–25 µg/mL, validated via recovery tests showing >98% accuracy . Method validation includes testing selectivity under thermal stress to confirm no peak overlap with degradation products or excipients .

Q. Basic: What are the key steps in this compound synthesis, and how have recent advancements improved efficiency?

Q: Describe the synthetic pathway for this compound and innovations that reduce step count or improve yield.
A: The synthesis involves a late-stage cyclopropanation and difluorination, enabling an 8-step process with 20% overall yield. Copper electrode-mediated multistep reactions accelerate synthesis by 20–50× compared to batch methods, reducing reaction time and resource use .

Q. Advanced: How do multivariate chemometric models enhance precision in quantifying this compound in complex matrices?

Q: What computational approaches address variability in spectrophotometric data for this compound-Sofosbuvir mixtures? A: Genetic algorithm-optimized partial least squares (GA-PLS) and artificial neural networks (ANN) improve predictive accuracy by selecting optimal wavelength combinations and reducing noise. These models achieve <2% relative error in concentration predictions for multi-component formulations .

Q. Advanced: What pharmacokinetic challenges arise from this compound’s pH-dependent solubility, and how are they mitigated?

Q: How does gastric pH affect this compound bioavailability, and what drug-interaction protocols are recommended? A: Elevated gastric pH reduces this compound solubility, lowering exposure by 30–40%. Clinical protocols mandate 4-hour separation from antacids and avoid high-dose PPIs (>20 mg omeprazole). Real-world data show proton pump inhibitor (PPI) use correlates with 5–6% lower SVR rates, necessitating dose timing adjustments .

Q. Advanced: How do contradictions between clinical trial and real-world data inform this compound-Sofosbuvir treatment duration?

Q: Why do some real-world studies report lower SVR rates for 8-week regimens despite non-inferiority in trials? A: While phase III trials showed 94–99% SVR for 8-week regimens in non-cirrhotic patients, real-world analyses identify confounding factors (e.g., cirrhosis misclassification, PPI use). Multivariate regression highlights albumin levels, bilirubin, and cirrhosis status as predictors of efficacy, supporting extended regimens for high-risk subgroups .

Q. Basic: How are stability-indicating methods validated for this compound in combination therapies?

Q: What stress conditions and parameters are used to validate this compound stability in fixed-dose combinations? A: Forced degradation studies under thermal (40–80°C), oxidative (H₂O₂), and photolytic conditions confirm method robustness. Acceptance criteria include ≤2% deviation in peak purity and resolution, with recovery rates of 98–102% across 50–150% concentration ranges .

Q. Advanced: How do multivariate analyses identify predictors of treatment failure in this compound-based regimens?

Q: What statistical methods reconcile disparate SVR outcomes in heterogeneous patient populations? A: Logistic regression of real-world cohorts (e.g., HCV-TARGET) identifies predictors like baseline HCV RNA >6 million IU/mL, hypoalbuminemia (<3.5 g/dL), and cirrhosis as risk factors. Machine learning models further stratify patients by IL28B genotype and fibrosis score to optimize regimen duration .

Q. Advanced: How do NS5A resistance-associated substitutions (RASs) impact this compound efficacy in HIV/HCV co-infection?

Q: What RASs are linked to virologic relapse, and how are they detected in resistant strains? A: Deep sequencing identifies Y93H/N RASs in NS5A, reducing this compound’s binding affinity by >100×. In co-infected patients, pre-existing RASs correlate with 2–4% relapse rates, necessitating resistance testing before salvage therapies (e.g., adding ribavirin or extending treatment to 24 weeks) .