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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

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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.
Keywords
PLUS SOFOSBUVIR, INFECTION, HCV, LEDIPASVIR/SOFOSBUVIR, PHARMACODYNAMICS, COMBINATION, RITONAVIR, PHASE-3, PLASMA, drug-drug interactions, hepatitis C virus, hepatitis C virus genotype 1, ledipasvir, pharmacokinetics, simeprevir, sofosbuvir, treatment-naive

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Chicago
Bourgeois, Stefan, Yves Horsmans, Frederik Nevens, Hans Van Vlierberghe, Christophe Moreno, Maria Beumont, Leen Vijgen, et al. 2017. “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.” Antimicrobial Agents and Chemotherapy 61 (12).
APA
Bourgeois, S., Horsmans, Y., Nevens, F., Van Vlierberghe, H., Moreno, C., Beumont, M., Vijgen, L., et al. (2017). 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. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 61(12).
Vancouver
1.
Bourgeois S, Horsmans Y, Nevens F, Van Vlierberghe H, Moreno C, Beumont M, et al. 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. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY. 2017;61(12).
MLA
Bourgeois, Stefan, Yves Horsmans, Frederik Nevens, et al. “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.” ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 61.12 (2017): n. pag. Print.
@article{8541835,
  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.},
  articleno    = {e01217-17},
  author       = {Bourgeois, Stefan and Horsmans, Yves and Nevens, Frederik and Van Vlierberghe, Hans and Moreno, Christophe and Beumont, Maria and Vijgen, Leen and van Eygen, Veerle and Luo, Donghan and Hillewaert, Vera and Van Remoortere, Pieter and van de Logt, Jolanda and Ouwerkerk-Mahadevan, Sivi},
  issn         = {0066-4804},
  journal      = {ANTIMICROBIAL AGENTS AND CHEMOTHERAPY},
  keyword      = {PLUS SOFOSBUVIR,INFECTION,HCV,LEDIPASVIR/SOFOSBUVIR,PHARMACODYNAMICS,COMBINATION,RITONAVIR,PHASE-3,PLASMA,drug-drug interactions,hepatitis C virus,hepatitis C virus genotype 1,ledipasvir,pharmacokinetics,simeprevir,sofosbuvir,treatment-naive},
  language     = {eng},
  number       = {12},
  pages        = {13},
  title        = {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},
  url          = {http://dx.doi.org/10.1128/AAC.01217-17},
  volume       = {61},
  year         = {2017},
}

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