Primary Effect on C201 Dose-dependency of effect Pharmacology activity using 4 dosing regimens Effect on C205 Sustained virologic response at Week sustained 72 in HCV infected virological subjects response C206 Proportion of treatment-experienced, HCV-infected subjects achieving SVR24 Secondary Effect on QTc C117 Thorough QT study Pharmacology Effect on C125 Cutaneous photosensitizing potential photosensitivity of multiple doses PD Interactions Norethindrone C124 Effect of simeprevir on hormone levels and after co-administration of ethinylestradiol norethindrone and ethinylestradiol Atorvastatin HPC1006 HMG-CoA reductase inhibitory activity and simvastatin in the presence and absence of simeprevir Methadone C110 PD effects of concurrent use of simeprevir and methadone TMC647055 HPC1001 Anti-viral activity following the of TMC647055 and simeprevir Population PD Target Multivariate analysis of prognostic and PK-PD population PPD factors analyses * Indicates the primary aim of the study. § Subjects who would be eligible to receive the drug if approved for the proposed indication. And adolescents if applicable. ‡ None of the pharmacodynamic studies had deficiencies that excluded their results from consideration. Summary of pharmacodynamics The information in the following summary is derived from conventional pharmacodynamic studies in humans unless otherwise stated. Mechanism of action Simeprevir is an inhibitor of the HCV NS3/4A protease, which is essential for viral replication. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Ki values of 0.5 nM and 1.4 nM, respectively.
Primary Pharmacology Effect on activity C201 Dose-dependency of effect using 4 dosing regimens Effect on sustained virological response C205 Sustained virologic response at Week 72 in HCV infected subjects C206 Proportion of treatment-experienced, HCV-infected subjects achieving SVR24 Secondary Pharmacology Effect on QTc C117 Thorough QT study Effect on photosensitivity C125 Cutaneous photosensitizing potential of multiple doses PD Interactions Norethindrone and ethinylestradiol C124 Effect of simeprevir on hormone levels after co-administration of norethindrone and ethinylestradiol Atorvastatin and simvastatin HPC1006 HMG-CoA reductase inhibitory activity in the presence and absence of simeprevir Methadone C110 PD effects of concurrent use of simeprevir and methadone TMC647055 HPC1001 Anti-viral activity following the of TMC647055 and simeprevir Population PD and PK-PD analyses Target population PPD Multivariate analysis of prognostic factors * Indicates the primary aim of the study. § Subjects who would be eligible to receive the drug if approved for the proposed indication. ‡ And adolescents if applicable. None of the pharmacodynamic studies had deficiencies that excluded their results from consideration. Summary of pharmacodynamics The information in the following summary is derived from conventional pharmacodynamic studies in humans unless otherwise stated. Mechanism of action Simeprevir is an inhibitor of the HCV NS3/4A protease, which is essential for viral replication. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Ki values of 0.5 nM and 1.4 nM, respectively.
auspar-simeprevir-141027-cer.docx