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Clinical Pharmacokinetics

Clinical Pharmacokinetics

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

Published:1 July 2015 DOI: 10.1007/s40262-015-0261-7 PMID: 25822283
Brian J Kirby, William T Symonds, Brian P Kearney, Anita A Mathias

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 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.

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Related products
Procduct Name CAS Molecular Formula Supplier Price
Sofosbuvir 1190307-88-0 C22H29FN3O9P 582 suppliers $50.00-$3990.00
2'-deoxy-2'-fluoro-2'-C-methyluridine 863329-66-2 C10H13FN2O5 436 suppliers $5.00-$1990.00

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