Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir

• Published in: Clinical pharmacokinetics 2015-07, Vol.54 (7), p.677-690
• Main Authors: Kirby, Brian J., Symonds, William T., Kearney, Brian P., Mathias, Anita A.
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Drug Interactions; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - metabolism; Humans; Internal Medicine; Medicine; Medicine & Public Health; Pharmacology/Toxicology; Pharmacotherapy; Prodrugs - pharmacokinetics; Prodrugs - pharmacology; Review Article; Sofosbuvir - pharmacokinetics; Sofosbuvir - pharmacology; Viral Nonstructural Proteins - antagonists & inhibitors
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-015-0261-7

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 sofosbuvir 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.