Indications
Sofosbuvir is a potent antiviral medication used in conjunction with other antiviral agents to treat chronic hepatitis C virus (HCV) infections. It is effective against HCV genotypes 1 through 6 and is also suitable for patients co-infected with HCV and HIV. For patients with varying degrees of liver cirrhosis, combination therapy might include ribavirin alone or ribavirin plus peg-interferon alfa. When co-administered with Ledipasvir, Sofosbuvir is indicated for genotypes 1, 4, 5, or 6 infections, specifically in patients without cirrhosis or with compensated cirrhosis. It may also be used with ribavirin to treat genotype 1 infections with decompensated cirrhosis, and for genotype 1 or 4 infections in liver transplant recipients without cirrhosis or with compensated cirrhosis. Additionally, in combination with Velpatasvir as Epclusa, Sofosbuvir is approved for adult patients with chronic HCV genotype 1 through 6 infections, either without cirrhosis or with compensated cirrhosis, and in conjunction with ribavirin if there is decompensated cirrhosis.
Pharmacodynamics
Sofosbuvir functions as a direct-acting antiviral agent (DAA) targeting the hepatitis C virus. It has been shown to significantly inhibit viral replication. Clinical studies have demonstrated that even when administered at three times the standard dosage, Sofosbuvir does not prolong the QTc interval to a clinically significant degree, indicating a favorable safety profile.
Absorption
Following oral administration, Sofosbuvir is rapidly absorbed, achieving peak plasma concentrations typically between 0.5 to 2 hours post-dose. The maximum concentration (Cmax) observed is approximately 567 ng/mL, reflecting its efficient absorption profile.
Metabolism
Investigations using in vitro human liver microsomes have elucidated that Sofosbuvir undergoes extensive metabolism. It is effectively processed by enzymes such as Cathepsin A (Cat A) and carboxyl esterase 1 (CES1), which mediate its cleavage. Subsequent activation involves 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. Cat A preferentially hydrolyzes the S-diastereomer of Sofosbuvir, whereas CES1 does not demonstrate stereoselectivity. This comprehensive metabolic pathway ensures the bioactivation of Sofosbuvir necessary for its antiviral efficacy.
Mechanism of Action
Sofosbuvir operates as a nucleotide analog inhibitor, targeting the NS5B RNA-dependent RNA polymerase of the Hepatitis C virus (HCV). Once inside the cell, it undergoes metabolic conversion to its active form, uridine analog triphosphate (GS-461203). This active compound is incorporated into the viral RNA by the NS5B polymerase, thereby acting as a chain terminator in RNA synthesis. Sofosbuvir effectively halts HCV replication by binding to the two magnesium ions located within the GDD active site motif of the NS5B polymerase, thereby disrupting further replication of the viral genetic material.
