title: Clinical Pharmacokinetics and Pharmacodynamics of Ledipasvir/Sofosbuvir, a Fixed-Dose Combination Tablet for the Treatment of Hepatitis C.
abstract: Ledipasvir/sofosbuvir (Harvoni®), a fixed-dose combination tablet of an NS5A inhibitor ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved in the US, European Union, Canada, and other regions for the treatment of chronic hepatitis C virus infection in adults. Following absorption, ledipasvir reaches maximum plasma concentrations (Tmax) 4-4.5 h post-dose and is eliminated with a terminal half-life (t1/2) of 47 h. Sofosbuvir undergoes intracellular activation to an active triphosphate GS-461203 (not detected in plasma) and ultimately to GS-331007, a predominant circulating metabolite, which is the primary analyte of interest in clinical pharmacology studies. Sofosbuvir is rapidly absorbed and eliminated from plasma (Tmax: 0.8-1 h; t1/2: 0.5 h). The peak plasma concentrations for GS-331007 are achieved between 3.5 and 4 h post-dose; the elimination t1/2for GS-331007 is 27 h. Ledipasvir/sofosbuvir exhibits a favorable clinical pharmacology profile; it can be administered once daily without regard to food and does not require dose modification in hepatitis C virus-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. The pharmacokinetic profiles of ledipasvir, sofosbuvir, and GS-331007 (predominant circulating metabolite of sofosbuvir) are not significantly affected by demographic variables; pharmacokinetic/pharmacodynamic analyses reveal no exposure-response relationships for efficacy or safety. The review summarizes the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic analyses for ledipasvir/sofosbuvir.
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA. polina.german@gilead.com.
authors.forename: Polina
authors.initials: P
authors.lastname: German
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Mathias
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Brainard
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kearney
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005449:Fluorenes / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D006207:Half-Life; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017093:Liver Failure / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051437:Renal Insufficiency / Q000378:metabolism; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; C000595958:ledipasvir, sofosbuvir drug combination; D014542:Uridine Monophosphate; D000069474:Sofosbuvir