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Sof osbuvir 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 [synthesis, A7533]. 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 [A19638, FDA Label].
Sofosbuvir is a direct-acting antiviral agent (pan-genotypic polymerase inhibitor) against the hepatitis C virus. HCV RNA replication is mediated by a membrane-associated multiprotein replication complex. The HCV polymerase (NS5B protein) is an RNA-dependent RNA polymerase (RdRp). It is the essential initiating and catalytic subunit of this replication complex and is critical for the viral replication cycle. There is no human homolog for HCV NS5B RdRp. Sofosbuvir is a monophosphorylated pyrimidine nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203). GS-461203 competes with natural nucleotides for incorporation (by HCV NS5B) into the nascent RNA strand during replication of the viral genome. GS-461203 differs from endogenous pyrimidine nucleotides in that it has been modified at the 2' position with the addition of a methyl and a fluoro functional group. Incorporation of GS-461203 into nascent RNA strongly reduces the efficiency of further RNA elongation by RdRp, resulting in premature termination of RNA synthesis. The stopping of viral replication leads to a rapid decline of HCV viral load and clearing of HCV levels in the body.

1.Ledipasvir/sofosbuvir in chronic hepatitis C: a guide to its use in the EU    Drugs & Therapy Perspectives    2015
Abstract:A single-tablet regimen of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir; Harvoni®) was recently approved in the EU. The phase 3 ION trials included treatment-naïve (ION-1 and -3) or treatment-experienced (ION-2) patients with chronic hepatitis C virus (HCV) genotype 1 infection; ≈20% of patients in ION-1 and -2 had cirrhosis, whereas none of the patients in ION-3 had cirrhosis. In ION-1, a 12-week regimen of ledipasvir/sofosbuvir achieved high rates of sustained virological response 12 weeks' post-treatment (SVR12) in treatment-naïve patients, with no additional benefit conferred by the addition of ribavirin or extending the treatment duration to 24 weeks. An 8-week regimen also achieved high SVR12 rates in patients with a baseline HCV RNA level of <6 million IU/mL in ION-3. High SVR12 rates were seen in treatment-experienced patients who received ledipasvir/sofosbuvir for 12 or 24 weeks in ION-2. Data also support the use of ledipasvir/sofosbuvir in chronic HCV genotype 4 infecti on, in HCV and HIV co-infection and, in combination with ribavirin, in patients with chronic HCV genotype 1 or 4 infection who have decompensated cirrhosis or are liver transplant recipients and in chronic HCV genotype 3 infection. Oral ledipasvir/sofosbuvir was generally well tolerated.
2.Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir    Clinical Pharmacokinetics    2015
Abstract:Sofosbuvir (SOVALDI®), a potent, once-daily, orally administered nucleotide analog prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase is approved in the USA, EU, Canada, and other regions for the treatment of HCV infection as a component of an antiviral treatment regimen. Sofosbuvir undergoes intracellular activation to form GS-461203 (active triphosphate, not detected in plasma), and ultimately the inactive, renally eliminated metabolite GS-331007. GS-331007 was identified as the primary analyte of interest for clinical pharmacology studies as it accounted for >90% of systemic drug-related material exposure, and provided comparable exposure–response relationships for viral kinetics as observed for sofosbuvir. GS-331007 and sofosbuvir exhibit linear pharmacokinetics with minimal accumulation upon multiple dosing. Compared to healthy subjects, HCV-infected patients had modestly lower (39 %) GS-331007 area under the plasma concentration--time curve (AUC) and higher sofosbuv ir AUC (60 %). Sofosbuvir can be administered without dose modification in HCV-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. Sofosbuvir has a low propensity for clinically significant drug interactions with common concomitant medications used by HCV- infected patients. Clinically significant alterations in GS-331007 or sofosbuvir exposures are limited to potent inducers of intestinal P-glycoprotein that may lower exposure. In HCV-infected patients, demographic variables do not significantly influence GS-331007 and sofosbuvir exposures and no consistent exposure --Response relationships were observed for efficacy or safety. This review focuses on the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic–pharmacodynamic relationships of sofosbuvir, and summarizes a number of drug interaction studies with important concomitant medications commonly used by HCV-infected patients.