PURPOSE: To describe the phase 1 and population pharmacokinetic investigations that support dosing recommendations for elbasvir/grazoprevir (EBR/GZR) in hepatitis C virus-infected people with advanced chronic kidney disease. METHODS: This was an open-label, two-part, multiple-dose trial (MK-5172 PN050; NCT01937975) in 24 non-HCV-infected participants with end-stage renal disease (ESRD) or severe renal impairment who received once-daily EBR 50 mg and GZR 100 mg for 10 days. Population pharmacokinetic analyses from the phase 3 C-SURFER study (PN052, NCT02092350) were also conducted. RESULTS: When comparing haemodialysis (HD) and non-HD days in participants with ESRD, geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for EBR and GZR AUC0-24 were 1.14 (1.08-1.21) and 0.97 (0.87-1.09). When comparing ESRD and healthy participants, GMRs (90% CIs) for EBR and GZR AUC0-24 were 0.99 (0.75-1.30) and 0.83 (0.56-1.22) on HD days, and 0.86 (0.65-1.14) and 0.85 (0.58-1.25) on non-HD days. GMRs (90% CIs) for AUC0-24 in participants with severe renal impairment relative to healthy controls were 1.65 (1.09-2.49) for GZR and 1.86 (1.38-2.51) for EBR. In population modelling of data from C-SURFER, absolute geometric means of steady-state EBR AUC0-24 were 2.78 and 3.07 μM*h (HD and non-HD recipients) and GZR AUC0-24 were 1.80 and 2.34 μM*h (HD and non-HD recipients). CONCLUSIONS: EBR/GZR represents an important treatment option for HCV infection in people with severe renal impairment and those with ESRD. No dosage adjustment of EBR/GZR is required in people with any degree of renal impairment, including those receiving dialysis.
PURPOSE: To describe the phase 1 and population pharmacokinetic investigations that support dosing recommendations for elbasvir/grazoprevir (EBR/GZR) in hepatitis C virus-infected people with advanced chronic kidney disease. METHODS: This was an open-label, two-part, multiple-dose trial (MK-5172 PN050; NCT01937975) in 24 non-HCV-infected participants with end-stage renal disease (ESRD) or severe renal impairment who received once-daily EBR 50 mg and GZR 100 mg for 10 days. Population pharmacokinetic analyses from the phase 3 C-SURFER study (PN052, NCT02092350) were also conducted. RESULTS: When comparing haemodialysis (HD) and non-HD days in participants with ESRD, geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for EBR and GZR AUC0-24 were 1.14 (1.08-1.21) and 0.97 (0.87-1.09). When comparing ESRD and healthy participants, GMRs (90% CIs) for EBR and GZR AUC0-24 were 0.99 (0.75-1.30) and 0.83 (0.56-1.22) on HD days, and 0.86 (0.65-1.14) and 0.85 (0.58-1.25) on non-HD days. GMRs (90% CIs) for AUC0-24 in participants with severe renal impairment relative to healthy controls were 1.65 (1.09-2.49) for GZR and 1.86 (1.38-2.51) for EBR. In population modelling of data from C-SURFER, absolute geometric means of steady-state EBR AUC0-24 were 2.78 and 3.07 μM*h (HD and non-HD recipients) and GZR AUC0-24 were 1.80 and 2.34 μM*h (HD and non-HD recipients). CONCLUSIONS: EBR/GZR represents an important treatment option for HCV infection in people with severe renal impairment and those with ESRD. No dosage adjustment of EBR/GZR is required in people with any degree of renal impairment, including those receiving dialysis.
Authors: Steven Harper; John A McCauley; Michael T Rudd; Marco Ferrara; Marcello DiFilippo; Benedetta Crescenzi; Uwe Koch; Alessia Petrocchi; M Katharine Holloway; John W Butcher; Joseph J Romano; Kimberly J Bush; Kevin F Gilbert; Charles J McIntyre; Kevin T Nguyen; Emanuela Nizi; Steven S Carroll; Steven W Ludmerer; Christine Burlein; Jillian M DiMuzio; Donald J Graham; Carolyn M McHale; Mark W Stahlhut; David B Olsen; Edith Monteagudo; Simona Cianetti; Claudio Giuliano; Vincenzo Pucci; Nicole Trainor; Christine M Fandozzi; Michael Rowley; Paul J Coleman; Joseph P Vacca; Vincenzo Summa; Nigel J Liverton Journal: ACS Med Chem Lett Date: 2012-03-02 Impact factor: 4.345
Authors: Vincenzo Summa; Steven W Ludmerer; John A McCauley; Christine Fandozzi; Christine Burlein; Giuliano Claudio; Paul J Coleman; Jillian M Dimuzio; Marco Ferrara; Marcello Di Filippo; Adam T Gates; Donald J Graham; Steven Harper; Daria J Hazuda; Qian Huang; Carolyn McHale; Edith Monteagudo; Vincenzo Pucci; Michael Rowley; Michael T Rudd; Aileen Soriano; Mark W Stahlhut; Joseph P Vacca; David B Olsen; Nigel J Liverton; Steven S Carroll Journal: Antimicrob Agents Chemother Date: 2012-05-21 Impact factor: 5.191
Authors: Miklos Z Molnar; Hazem M Alhourani; Barry M Wall; Jun L Lu; Elani Streja; Kamyar Kalantar-Zadeh; Csaba P Kovesdy Journal: Hepatology Date: 2015-03-20 Impact factor: 17.425
Authors: Judith I Tsui; Eric Vittinghoff; Michael G Shlipak; Daniel Bertenthal; John Inadomi; Rudolph A Rodriguez; Ann M O'Hare Journal: Arch Intern Med Date: 2007-06-25
Authors: Y Zhang; L Zhang; S Abraham; S Apparaju; T-C Wu; J M Strong; S Xiao; A J Atkinson; K E Thummel; J S Leeder; C Lee; G J Burckart; L J Lesko; S-M Huang Journal: Clin Pharmacol Ther Date: 2008-11-19 Impact factor: 6.875
Authors: Craig A Coburn; Peter T Meinke; Wei Chang; Christine M Fandozzi; Donald J Graham; Bin Hu; Qian Huang; Stacia Kargman; Joseph Kozlowski; Rong Liu; John A McCauley; Amin A Nomeir; Richard M Soll; Joseph P Vacca; Dahai Wang; Hao Wu; Bin Zhong; David B Olsen; Steven W Ludmerer Journal: ChemMedChem Date: 2013-10-14 Impact factor: 3.540