Pharmacokinetic Interactions between Simeprevir and Ledipasvir in Treatment-Naive Hepatitis C Virus Genotype 1-Infected Patients without Cirrhosis Treated with a Simeprevir-Sofosbuvir-Ledipasvir Regimen

Abstract

Interactions between simeprevir (hepatitis C virus [HCV] NS3/4A protease inhibitor) and ledipasvir (HCV NS5A replication complex inhibitor) were investigated in treatment-naive HCV genotype 1-infected patients without cirrhosis, treated with simeprevir-sofosbuvir-ledipasvir in a two-panel, phase 2, open-label study. 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 to 14; steady-state pharmacokinetics (PK) of simeprevir was 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 to 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-fold (2.0- to 2.8-fold) and 3.1-fold (2.4- to 3.8-fold) for simeprevir, respectively (panel 1), and 1.6-fold (1.4- to 1.9-fold) and 1.7-fold (1.6- to 2.0-fold) for ledipasvir, respectively (panel 2), in the presence versus the absence of the other drug. All patients achieved sustained virologic responses 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. (This study has been registered at ClinicalTrials.gov under registration no. NCT02421211.).

Keywords: drug-drug interactions; hepatitis C virus; hepatitis C virus genotype 1; ledipasvir; pharmacokinetics; simeprevir; sofosbuvir; treatment-naive.

Copyright © 2017 American Society for Microbiology.

Figures

FIG 1

Mean (standard deviation [SD]) plasma concentration-time curves of simeprevir (a) and ledipasvir (b) at day 14 and day 28 (ITT population). ITT, intent to treat; LDV, ledipasvir; QD, once daily: SMV, simeprevir; SOF, sofosbuvir.

FIG 2

On-treatment and posttreatment virologic responses in HPC2017 (ITT population). EOT, end of treatment; HCV, hepatitis C virus; ITT, intent-to-treat; SVR12, sustained virologic response 12 weeks after EOT.

FIG 3

Study design. aPK sampling occurred on day 14 and day 28. LDV, ledipasvir; PK, pharmacokinetic; QD, once daily; SMV, simeprevir; SOF, sofosbuvir.