Pharmacokinetic Interactions between Simeprevir and Ledipasvir in Treatment-naïve Hepatitis C virus Genotype 1-infected Patients without Cirrhosis Treated with a Simeprevir/Sofosbuvir/Ledipasvir Regimen

Interactions between simeprevir (hepatitis C virus [HCV] NS3/4A protease inhibitor) and ledipasvir (HCV NS5A replication complex inhibitor) were investigated in treatment-naïve HCV genotype 1-infected patients without cirrhosis, treated with simeprevir/sofosbuvir/ledipasvir in a two-panel, Phase 2, open-label study (NCT02421211). Patients had stable background treatment with sofosbuvir (400 mg once daily [QD]). In Panel 1 (N=20), the effect of ledipasvir (90 mg QD) on simeprevir (150 mg QD) was studied. Patients received simeprevir and sofosbuvir from Days 1--14; steady-state pharmacokinetics (PK) of simeprevir were assessed (Day 14). On Day 15, ledipasvir was added and steady-state PK of simeprevir in the combination was evaluated (Day 28). In Panel 2 (N=20), the effect of simeprevir on ledipasvir was investigated. From Days 1--14, patients received ledipasvir and sofosbuvir and steady-state PK of ledipasvir was assessed (Day 14). On Day 15, simeprevir was added and a full PK profile was obtained (Day 28). The least squares mean maximum plasma concentration and area under the concentration--time curve (90% confidence interval) increased 2.3- (2.0-2.8) and 3.1- (2.4-3.8) fold for simeprevir, respectively, (Panel 1); and 1.6- (1.4-1.9) and 1.7- (1.6-2.0) fold for ledipasvir, respectively (Panel 2), in the presence versus the absence of the other drug. All patients achieved sustained virologic response 12 weeks after treatment end. Adverse events, mainly Grade 1/2, occurred in 80% of patients; the most common was photosensitivity (45%). Due to the magnitude of interaction and the limited amount of safety data available, the use of this treatment combination is not recommended.status: publishe