HEPCVIR-L is a fixed-dose combination (FDC) of ledipasvir and sofosbuvir, which are direct-acting antiviral agents against the hepatitis C virus (HCV). Ledipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine
Thorough QT studies have been conducted for ledipasvir and sofosbuvir. The effect of ledipasvir 120 mg twice daily (2.67 times the maximum recommended dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose, placebo- and active-controlled (moxifloxacin 400 mg), three-period, crossover thorough QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the maximum recommended dosage), ledipasvir does not prolong QTc interval to any clinically relevant extent. The effect of sofosbuvir 400 mg (maximum recommended dosage) and 1,200 mg (three times the maximum recommended dosage) on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg), four-period, crossover thorough QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.
The pharmacokinetic properties of ledipasvir, sofosbuvir and the predominant circulating metabolite, GS-331007, have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of ledipasvir -sofosbuvir FDC, ledipasvir median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~0.8 to 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed between 3.5 to 4 hours post-dose.
Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric mean steady-state AUC0-24 for ledipasvir (N=2,113), sofosbuvir (N=1,542), and GS-331007 (N=2,113) were 7,290, 1,320 and 12,000 ng•hr/mL, respectively. Steady-state Cmax for ledipasvir, sofosbuvir, and GS-331007 were 323, 618 and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=191), ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in HCV-infected subjects.