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Clinical Pharmacokinetics and Pharmacodynamics of Ledipasvir/Sofosbuvir, a Fixed-Dose Combination Tablet for the Treatment of Hepatitis C

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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 (T max) 4–4.5 h post-dose and is eliminated with a terminal half-life (t 1/2) 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 (T max: 0.8–1 h; t 1/2: 0.5 h). The peak plasma concentrations for GS-331007 are achieved between 3.5 and 4 h post-dose; the elimination t 1/2 for 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.

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Correspondence to Polina German.

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Polina German, Anita Mathias, Diana Brainard, and Brian P. Kearney are employees of Gilead, contributed significant to the design, conduct, analyses and interpretation of data, and were involved in the preparation, review, and approval of this article. Gilead Sciences, Inc. provided funding for research presented in this article. Polina German, Anita Mathias, Diana Brainard, and Brian P. Kearney are stockholders of Gilead Sciences, Inc. Informed consent was obtained from each subject before initiation of any screening procedures. The study protocol and informed consent documents were reviewed and approved by a duly constituted institutional review board before study initiation in accordance with the basic principles defined in the US 21 CFR Part 312.20 and the principles enunciated in the Declaration of Helsinki.

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German, P., Mathias, A., Brainard, D. et al. Clinical Pharmacokinetics and Pharmacodynamics of Ledipasvir/Sofosbuvir, a Fixed-Dose Combination Tablet for the Treatment of Hepatitis C. Clin Pharmacokinet 55, 1337–1351 (2016). https://doi.org/10.1007/s40262-016-0397-0

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