Sofosbuvir

The synthesis of sofosbuvir involves several steps, including the preparation of key intermediates and the final coupling reaction. One of the synthetic routes involves the use of (2’R)-2’-deoxy-2’-fluoro-2’-methyluridine as a starting material. This compound is reacted with other raw materials in an organic solvent in the presence of a Lewis acid and an alkali to produce this compound . The reaction conditions are mild, and the process is suitable for large-scale industrial production .

Another method involves a more stereoselective preparation, which allows for the production of the desired isomer without the need for intermediate separation. This method reduces production costs and is also suitable for industrialized production .

Sofosbuvir undergoes various chemical reactions, including:

Oxidation: This compound can be oxidized to form its active metabolite, GS-461203, which is a triphosphate.

Reduction: Reduction reactions are not commonly associated with this compound.

Substitution: This compound can undergo substitution reactions, particularly involving the fluorine atom on the furanose ring.

Common reagents and conditions used in these reactions include organic solvents, Lewis acids, and alkali . The major products formed from these reactions include the active triphosphate form of this compound and other intermediates used in its synthesis .

Treatment of Chronic Hepatitis C

Sofosbuvir is primarily indicated for the treatment of chronic hepatitis C across all genotypes. Its effectiveness has been demonstrated in various clinical trials:

• Efficacy Across Genotypes : this compound-based regimens have shown high SVR rates, particularly in genotypes 1 and 2, with studies reporting SVR rates exceeding 90% in treatment-naïve patients .
• Challenges with Genotype 3 : Despite its overall effectiveness, genotype 3 infections present challenges, with lower SVR rates reported, especially in patients with cirrhosis .

Special Populations

This compound has been evaluated for use in special populations, including those with advanced chronic kidney disease (CKD):

• Patients with CKD : A systematic review indicated that this compound-based regimens are safe and effective for patients with stage 4–5 CKD. The pooled SVR rate was found to be 99%, highlighting its utility even in patients with significant renal impairment .
• Co-infection Scenarios : this compound is also effective in patients co-infected with HIV or those who have previously failed other DAA therapies, demonstrating its versatility in complex clinical situations .

Real-World Efficacy

A study involving a cohort of decompensated cirrhotic patients treated with this compound/Velpatasvir reported an impressive SVR12 rate of 94.4%. This highlights the drug's effectiveness even in challenging patient populations .

Phase III Trials

In a Phase III trial conducted in Japan, all participants receiving an all-oral regimen containing this compound achieved undetectable HCV levels by week four, underscoring its rapid action against the virus .

Safety Profile

This compound is generally well-tolerated, but some adverse events have been reported:

• Common Adverse Events : Fatigue, headache, and anemia are frequently observed but are typically manageable. Serious adverse events occur at a rate of approximately 9% in clinical settings .
• Monitoring Recommendations : Close monitoring of renal function is advised for patients with CKD during treatment to mitigate risks associated with potential renal impairment .

Comparative Effectiveness

A systematic review comparing this compound-based regimens with and without ribavirin found that while adding ribavirin may enhance SVR rates in some cases, it also increases the risk of serious adverse events . This underscores the importance of tailoring treatment regimens to individual patient needs.

Sofosbuvir is a prodrug that is metabolized into its active form, GS-461203, within the body . This active form inhibits the HCV NS5B RNA-dependent RNA polymerase by acting as a defective substrate, thereby terminating the viral RNA chain and preventing replication . The inhibition of this enzyme is crucial for the suppression of HCV replication and the achievement of a sustained virologic response .

Sofosbuvir is often compared with other direct-acting antiviral agents, such as:

Ledipasvir: Used in combination with this compound for the treatment of HCV.

Velpatasvir: Another antiviral agent used in combination with this compound for pan-genotypic treatment of HCV.

Daclatasvir: Used in combination with this compound for the treatment of HCV.

Simeprevir: Used in combination with this compound for the treatment of HCV.

Remdesivir: An antiviral agent used for the treatment of COVID-19, which also targets RNA-dependent RNA polymerase.

This compound is unique in its high barrier to resistance development and its effectiveness across multiple HCV genotypes . Its combination with other antiviral agents enhances its efficacy and broadens its application in treating various HCV genotypes .

Basic Research Questions

Q. What validated analytical methods are available for quantifying sofosbuvir in pharmaceutical formulations or biological matrices?

• Methodology : Reverse-phase high-performance liquid chromatography (RP-HPLC) is widely used, with parameters optimized via Quality by Design (QbD) approaches. For example, a QbD-based method optimized mobile phase ratio (e.g., acetonitrile:buffer), buffer pH (e.g., phosphate buffer at pH 4.5–6.5), and column type (C18 or phenyl-hexyl) using Design-Expert® software. This method achieved retention times of 2.5–4.5 minutes, peak tailing <2, and theoretical plates >5,000 .
• Validation : Include specificity, linearity (e.g., 10–100 µg/mL), precision (RSD <2%), and robustness against pH or flow-rate variations .

Q. How are clinical trials for this compound-based regimens designed to assess efficacy against HCV genotypes?

• Design : Trials often use randomized, controlled designs with stratification by genotype (e.g., genotype 2 vs. 3), cirrhosis status, and prior treatment history. For example, the VALENCE trial extended treatment duration for genotype 3 from 12 to 24 weeks after interim analysis showed improved sustained virologic response (SVR) rates (85% vs. 56% in cirrhotic patients) .
• Endpoints : Primary endpoints include SVR at 12 weeks post-treatment (SVR12), analyzed via intention-to-treat. Secondary endpoints may address adverse events (e.g., headache, fatigue) and subgroup efficacy .

Q. What statistical tools are employed to analyze this compound clinical trial data?

• Tools : SPSS or R for descriptive statistics (mean, SD) and inferential tests (Chi-square, paired t-tests). For example, a study comparing dual (this compound + ribavirin) vs. triple therapy (with peginterferon) used a p-value ≤0.05 to define significance in SVR rates .

Advanced Research Questions

Q. How can multivariate chemometric models resolve challenges in quantifying this compound in combination therapies (e.g., with ledipasvir)?

• Approach : Genetic algorithm-partial least squares (GA-PLS) and artificial neural networks (ANN) improve precision in spectral data analysis. For instance, GA-PLS applied to UV-Vis spectra (200–400 nm) of this compound/ledipasvir mixtures achieved recovery rates of 98–102% with RSD <1.5% .
• Validation : Cross-validate models using synthetic mixtures and real-world samples, ensuring minimal interference from excipients or metabolites .

Q. What experimental designs optimize this compound-loaded lipid nanocarriers for enhanced bioavailability?

• Design : A 2³ factorial design evaluates factors like lipid concentration (X1), cholesterol content (X2), and centrifugation speed (X3). Responses such as drug entrapment efficiency (DEE >80%) and particle size (<200 nm) are modeled via Design-Expert® software. For example, high X1 and low X3 maximized DEE while minimizing particle size .
• Characterization : Use dynamic light scattering (DLS) for size distribution and in vitro release studies in simulated intestinal fluid (pH 6.8) .

Q. How do researchers address contradictory efficacy data for this compound across HCV genotypes?

• Analysis : Stratify data by genotype and cirrhosis status. Genotype 3 patients show lower SVR rates (68% with cirrhosis vs. 91% without) compared to genotype 2 (93% SVR). Meta-analyses or pooled data from trials like FISSION and NEUTRINO can reconcile discrepancies by adjusting for covariates (e.g., viral load, IL28B polymorphisms) .

Q. What advanced bioanalytical techniques quantify this compound metabolites (e.g., GS-331007) in plasma?

• Technique : Online SPE-LC coupled to Q-Exactive HRMS enables sensitive detection (LOQ: 1 ng/mL) using t-MS² or t-SIM modes. This method validated this compound’s pharmacokinetics, including its short half-life (0.4 hours) and metabolite GS-331007’s prolonged half-life (27 hours) .

Q. How can QbD principles improve robustness in this compound assay development?

• Implementation : Define critical quality attributes (CQAs) like retention time and peak symmetry. Use risk assessment (e.g., Ishikawa diagrams) to prioritize factors (mobile phase, column temperature). A 14-run experimental design identified optimal conditions (e.g., pH 5.0, 70:30 acetonitrile:buffer) with robustness confirmed via intermediate precision testing (RSD <1.5%) .

Q. Methodological Frameworks

Q. How to formulate a research question for this compound studies addressing gaps in HCV management?

• Process : Start with systematic reviews to identify gaps (e.g., optimizing regimens for genotype 4). Narrow questions using PICOT criteria: Population (HCV genotype 4 patients), Intervention (this compound/velpatasvir), Comparison (historical interferon-based therapies), Outcome (SVR12), Time (12 weeks). Sub-questions may explore resistance-associated substitutions (RASs) or cost-effectiveness in low-resource settings .

Q. What strategies mitigate bias in this compound clinical trials with open-label designs?

• Controls : Use blinded endpoint adjudication committees and centralized PCR testing for HCV RNA. For example, the SYNERGY trial achieved 95% SVR12 in genotype 4 patients by masking laboratory analysts to treatment allocation .