Sofosbuvir

Details:

density     1.41
pka    9.39±0.10(Predicted)
CAS DataBase Reference    1190307-88-0
Safety Information
HS Code     29339900
Hazardous Substances Data    1190307-88-0(Hazardous Substances Data)

Mechanism of action and resistance    Sofosbuvir is a pyrimidine nucleotide analogue (Fig. 1) that inhibits HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication[11, 12], Sofosbuvir is a prodrug that undergoes intracellular metabolism in human hepatocytes to a pharmacologically active uridine triphosphate form (GS-461203)[11-14]. GS-461203 is incorporated into HCV RNA by NS5B polymerase where it acts as a chain terminator[11, 12]. In vitro, the GS-461203 concentration leading to 50 % inhibition of the polymerase activity of recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a ranged from 0.7 to 2.6 micromolar per liter. A rapid rate of viral decline was seen with Sofosbuvir[20]. It was estimated that 99 and 99.9 % of final effectiveness would be reached in a mean 0.8 and 2 days, respectively[20]. HCV RNA levels declined in a biphasic manner[20].
Sofosbuvir has a high genetic barrier to resistance[15]. Studies have found that resistance-associated variants (including the primary sofosbuvir resistance mutation in NS5B, S282T) were not detected in any patient receiving sofosbuvir in combination with ribavirin with or without peginterferon-alpha[15, 16]. However, the S282T resistance mutation was detected in one patient with HCV genotype 2b infection who received sofosbuvir monotherapy. Although L159F and V321A substitutions were detected in some patients with HCV genotype 3a infection who received sofosbuvir-containing regimens in phase III trials, these substitutions were not associated with changes in phenotypic susceptibility of sofosbuvir[12]. In patients with HCV genotype 1a or 2b infection and HCC who received sofosbuvir and ribavirin for up to 48 weeks while awaiting liver transplantation, the L159F substitution emerged in multiple patients who experienced virological failure (breakthrough and relapse)[12]. The presence of L159F and/or C316N substitutions at baseline was also associated with post-transplant virological breakthrough and relapse in multiple patients with HCV genotype 1b infection[12].
HCV replicons expressing the S282T resistance mutation showed low level resistance to sofosbuvir, but retained susceptibility to ribavirin and other classes of direct-acting antivirals, including NS5A inhibitors[17]. Sofosbuvir retained full activity against the nucleoside inhibitor resistance-associated variants L159F and L320F, the ribavirin resistance-associated variants T390I and F415Y, and against clinically relevant protease inhibitor, non-nucleoside inhibitor and NS5A inhibitor resistance-associated variants[18, 19]