Sofosbuvir 400mg & Daclatasvir 60mg Tablets: How to use?

Summary

Sofosbuvir & Daclatasvir is a direct-acting antiviral agent used to treat specific hepatitis C virus (HCV) infections in combination with other antiviral agents.

Buy Now

Background

Sofosbuvir & Daclatasvir (tradename Sovaldi) is a direct-acting antiviral medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States and affecting 72% of all chronic HCV patients. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as sofosbuvir. As a prodrug nucleotide analog, Sofosbuvir is metabolized into its active form as the antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate (also known as GS-461203), which acts as a defective substrate for NS5B (non-structural protein 5B) Synthesis. NS5B, an RNA-dependent RNA polymerase, is essential for the transcription of Hepatitis C viral RNA and for its high replicative rate and genetic diversity. Sofosbuvir and other direct-acting antivirals are therefore very potent options for the treatment of Hepatitis C, as they exhibit a high barrier to the development of resistance. This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid development of resistance has proven to be an important cause of therapeutic failure.

In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend Sofosbuvir as first-line therapy in combination with other antivirals for all six genotypes of Hepatitis C. Depending on the genotype, sofosbuvir is often used in combination with other antivirals such as Ledipasvir, Velpatasvir, Daclatasvir, Simeprevir, Elbasvir, Grazoprevir, Ribavirin, Peginterferon alfa-2a, or Peginterferon alfa-2b with the intent to cure or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection are associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality. Treatment with direct-acting antivirals such as sofosbuvir is associated with very minimal side effects, with the most common being headache and fatigue Label. Lack of significant side effects and short duration of therapy is a considerable advantage over older interferon- and ribavirin-based regimens, which were limited by infusion site reactions, reduced blood count, and neuropsychiatric effects.

Since 2014, sofosbuvir has been available as a fixed-dose combination product with Ledipasvir (tradename Harvoni) used for the treatment of chronic Hepatitis C. Approved in October 2014 by the FDA, Harvoni is indicated for the treatment of HCV genotypes 1, 4, 5, and 6 with or without Ribavirin depending on the level of liver damage or cirrhosis Label. When combined together, ledipasvir and sofosbuvir as the combination product Harvoni have been shown to achieve an SVR between 93 and 99% after 12 weeks of treatment 3. Its use has also proven successful in the treatment of HCV in patients co-infected with HIV.

Sofosbuvir is also available as a fixed-dose combination product with Velpatasvir as the commercially available product Epclusa. First approved in June 2016, Epclusa is the first combination of HCV products indicated for the treatment of all genotypes of Hepatitis C with or without cirrhosis. Epclusa is also currently the most potent HCV antiviral medication on the market with a sustained virologic response (SVR) after 12 weeks of therapy of 93-99% depending on genotype and level of cirrhosis. Both Canadian and American guidelines list Epclusa as a first-line recommendation for all genotypes of HCV.

Notably, sofosbuvir has come under intense scrutiny since its release to market in 2013. With the price per pill set at $1000, a 12-week treatment can cost upwards of $84,000 per patient.

Structure

Sofosbuvir

---

Daclatasvir

Indication

Sofosbuvir is used in combination therapy with other antiviral medications to treat chronic hepatitis C virus (HCV) infected patients with HCV genoptypes 1-6 and to treat HCV and HIV, co-infected patients. Depending on the level of cirrhosis or decompensation, combination therapy can also include either ribavirin alone or ribavirin and peg-interferon alfa.

When used in combination with Ledipasvir as the combination product Harvoni, sofosbuvir has the following indications: treatment of genotypes 1, 4, 5, or 6 infections without cirrhosis or with compensated cirrhosis; in combination with Ribavirin for genotype 1 infection with decompensated cirrhosis; or in combination with Ribavirin for the treatment of genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis.

When used in combination with Velpatasvir as the combination product Epclusa, sofosbuvir is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotypes 1, 2, 3, 4, 5, or 6 infections without cirrhosis or with compensated cirrhosis, or in combination with Ribavirin if associated with decompensated cirrhosis.

Resistance: Reduced susceptibility to sofosbuvir has been associated with the NS5B substitution mutation S282T.

Pharmacodynamics

Sofosbuvir & Daclatasvir acts against HCV and is categorized as a direct-acting antiviral agent (DAA).

At a dose 3 times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent Label.

Resistance: Reduced susceptibility to sofosbuvir has been associated with the NS5B substitution mutation S282T.

Mechanism of action

Sofosbuvir & Daclatasvir is a nucleotide analog inhibitor, which specifically inhibits HCV NS5B (non-structural protein 5B) RNA-dependent RNA polymerase. Following intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), sofosbuvir incorporates into HCV RNA by the NS5B polymerase and acts as a chain terminator Synthesis. More specifically, Sofosbuvir prevents HCV viral replication by binding to the two Mg2+ ions present in HCV NS5B polymerase's GDD active site motif and preventing further replication of HCV genetic material.

Absorption

When given orally, sofosbuvir reaches its maximum plasma concentration in about 0.5 to 2 hours with a maximal concentration (Cmax) of 567 ng/mL.

Volume of distribution

The volume of distribution for sofosbuvir has yet to be determined

Protein binding

Sofosbuvir is approximately 61-65% bound to human plasma proteins

Metabolism

In vitro studies in the human liver, microsomes showed that sofosbuvir was an efficient substrate for Cathepsin A (Cat A) and carboxylesterase 1 (CES1). Sofosbuvir was cleaved by CatA and CES1 and subsequent activation steps included amino acid removal by histidine triad nucleotide-binding protein 1 (HINT1) and phosphorylation by uridine monophosphate-cytidine monophosphate (UMP-CMP) kinase and nucleoside diphosphate (NDP) kinase. In vitro data indicated that Cat A preferentially hydrolysed sofosbuvir (the S-diastereomer) while CES1 did not exhibit stereoselectivity.

Hover over products below to view reaction partners

• Sofosbuvir

  • GS-56650

    • GS-606965

      • GS-461203

Route of elimination

Sofosbuvir is eliminated by three routes: urine ( 80%), feces (14%), and respiration (2.5%); however, elimination through the kidneys is the major route.

Half-life

Sofosbuvir has a terminal half-life of 0.4 hours.

Clearance

The clearance of sofosbuvir has yet to be determined.

Toxicity

Sofosbuvir, as a single agent, has very mild toxicity. The most common adverse reactions are headaches and fatigue. The FDA Label currently warns of a risk of symptomatic bradycardia when Epclusa is used in combination with amiodarone.

Affected organisms

• Hepatitis C Virus