Introduction
Sofosbuvir is a direct-acting antiviral (DAA) used in combination with other antiviral agents for the treatment of chronic hepatitis C virus (HCV) infection. It is a nucleotide analog prodrug that is converted to an active metabolite, which inhibits the viral NS5B RNA-dependent RNA polymerase, preventing viral RNA replication and leading to viral clearance.
Sofosbuvir is effective against multiple HCV genotypes and is commonly used in fixed-dose combinations with other antiviral agents, such as ledipasvir or velpatasvir. Combination therapy with sofosbuvir achieves high sustained virologic response (SVR) rates, offering a well-tolerated and highly effective treatment for chronic hepatitis C.
Uses
Sofosbuvir is a direct-acting antiviral agent used to treat specific hepatitis C virus (HCV) infections in combination with other antiviral agents.
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 infection 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 infection 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 .
Associated Conditions
Pharmacodynamics
Sofosbuvir 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 .
Mechanism of Action
Sofosbuvir is 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 . 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 .
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 headache and fatigue. The FDA Label currently warns of a risk of symptomatic bradycardia when Epclusa is used in combination with amiodarone .
Food Interactions
- Take with or without food.
Dosage
Recommended combination therapy: (HCV Mono-infected and HCV/HIV-1 Co-infected)-
- Genotype 1 or 4: Sofosbuvir + Peginterferon alfa + Ribavirin for 12 weeks
- Genotype 2: Sofosbuvir + Ribavirin for 12 weeks
- Genotype 3: Sofosbuvir + Ribavirin for 24 weeks
Should be used in combination with Ribavirin for treatment of CHC in patients with hepatocellular carcinoma awaiting liver transplantation for up to 48 weeks or until liver transplantation whichever occurs first
A dose recommendation cannot be made for patients with severe renal impairment or end stage renal disease
