General Description

Sofosbuvir is an innovative antiviral medication primarily used to treat hepatitis C. It is classified as a phosphoramidate prodrug with a low molecular weight of 529.45 grams per mole and a high solubility profile suitable for oral administration. Marketed as SOVALDI by Gilead Sciences, sofosbuvir is available in 400-milligram film-coated tablets. Pharmacokinetically, sofosbuvir shows favorable intestinal absorption with about 80% of an oral dose reaching systemic circulation in humans, and it is primarily excreted as an inactive metabolite through the kidneys. These characteristics highlight the drug's efficacy in managing hepatitis C and its practicality in clinical settings.

Figure 1. Sofosbuvir

Characteristics

Introduction to Sofosbuvir

Sofosbuvir is a groundbreaking antiviral medication primarily used in the treatment of hepatitis C. The chemical name for sofosbuvir is (S)Isopropyl 2-((S)-(((2R, 3R, 4R, 5R)-5-(2,4-dioxo 3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2yl)methoxy)(phenoxy)phosphorylamino) propanoate. With a low molecular weight of 529.45 grams per mole, sofosbuvir has the molecular formula C22H29FN3O9P. This compound is classified as a phosphoramidate prodrug, characterized by its weak acid properties, high solubility, and low permeability. In accordance with the Biopharmaceutics Classification System, sofosbuvir falls under Class 3, indicating its solubility profile and absorption characteristics suited for oral administration. ¹

HCV Treatment

Chronic hepatitis C remains a major public health concern with a prevalence of more than 1% worldwide. Of late, with the discovery of newer drugs, chronic HCV treatment has touched new dimensions. The treatment has progressed from Interferons to Pegylated interferon (Peg IFN) based therapy, with or without ribavirin to treatment with orally active Direct Acting Antivirals (DAA) with Peg IFN and ribavirin and eventually to various combinations of DAA, without IFN. Introduction of newer DAAs has transfigured the treatment of chronic HCV. Chronic HCV patients with advanced liver disease, psychiatric condition, anemia or autoimmune diseases, not eligible for Peg IFN based therapy have a ray of hope now. Amongst all DAAs, nucleoside inhibitors have been the most promising agent. Thus the present review focuses on Sofosbuvir, one of the most effective nucleoside inhibitors; in terms of potency, resistance profile, activity against all genotypes of HCV and adverse effects. FDA approved Sofobuvir for clinical use in 2013. Chemically, it is 2'-deoxy-2'-α-fluoro-β-Cmethyluridine- 5'-triphosphate; a phosphoramidate prodrug that is activated by enzyme present in human liver. It is a highly potent inhibitor of HCV NS5B polymerase. Efficacy of the Sofosbuvir has been established in various phase 2 and phase 3 clinical trials like PROTON, ELECTRON, FUSION, POSITRON etc. Sofosbuvir has a good safety profile with few mild to moderate adverse effects. Evidence reveals that sofosbuvir has substantial impact on the treatment of HCV.¹

Pharmacokinetics

Preclinical Pharmacokinetics

Sofosbuvir demonstrates promising pharmacokinetics through its favorable intestinal absorption and extensive metabolism observed in preclinical studies. When administered orally in portal vein cannulated dogs, the bioavailability of sofosbuvir was determined to be 9.89%. This figure indicates that approximately 36.4% of the administered dose was absorbed, while 74% underwent hepatic extraction. Importantly, the data reveal that sofosbuvir is primarily excreted in urine as an inactive metabolite, emphasizing its metabolic pathway and the role of the kidneys in eliminating this drug. Overall, the preclinical findings highlight the efficient absorption and metabolism characteristics of sofosbuvir that contribute to its therapeutic effectiveness. ²

Clinical Pharmacokinetics

In human subjects, clinical pharmacokinetic studies indicate that about 80% of an orally administered dose of sofosbuvir is absorbed into the systemic circulation, with a median time to peak concentration occurring at approximately 1 hour. Following oral administration, peak concentration of sofosbuvir typically occurs within 0.5 to 2 hours, while the peak of its inactive metabolite, GS-331007, is reached between 2 to 4 hours post-dose. The plasma protein binding of sofosbuvir in healthy individuals is approximately 82%, which slightly increases to 85% in patients with end-stage renal disease. The rapid elimination of sofosbuvir is characterized by a median half-life ranging from 0.48 to 0.75 hours, while metabolite GS-331007 exhibits longer pharmacokinetic parameters, including a half-life of approximately 7.27 to 11.80 hours. ²

Pharmacokinetic Characteristics of Sofosbuvir and Its Metabolites

Sofosbuvir and its inactive nucleoside metabolite GS-331007 demonstrate time-independent, near-linear pharmacokinetics in patients infected with hepatitis C virus, mirroring results seen in healthy subjects. The primary route of elimination for GS-331007 is renal, accounting for around 78% of its excretion, while the remainder is eliminated either as unchanged drug or through feces. Notably, in vitro studies suggest that sofosbuvir acts as a substrate for P-glycoprotein, yet it does not interact with the cytochrome P450 system, ensuring a smooth pharmacokinetic profile. Furthermore, food has a minimal impact on the extent of sofosbuvir absorption, though high-fat meals can slow its absorption rate. As articulated in prescribing information in the United States, dosing of sofosbuvir can be administered without regard to food. These pharmacokinetic characteristics underline the drug's efficiency and help guide appropriate therapeutic use in clinical practice. ²