UNLABELLED: Mericitabine (RG7128) is a nucleoside polymerase inhibitor (NPI), which requires intracellular uptake and phosphorylation to two active triphosphates. Mathematical modeling has provided important insights for characterizing hepatitis C virus (HCV) RNA decline and estimating in vivo effectiveness of antiviral agents; however, it has not been used to characterize viral kinetics with NPIs. HCV RNA was frequently measured in 32 treatment-experienced patients infected with HCV genotype 1 during and after mericitabine monotherapy for 14 days with 750 mg or 1500 mg administered once (qd) or twice daily (bid). The initial decline of HCV RNA was typically slower than with interferon-α or protease inhibitors, and 12 patients presented a novel pattern of HCV RNA kinetics characterized by a monophasic viral decline. Viral kinetics could be well fitted by assuming that the effectiveness in blocking viral production gradually increased over time to reach its final value, ε(2), consistent with previous accumulation time estimates of intracellular triphosphates. ε(2) was high with bid dosing (mean 750 mg and 1500 mg: 98.0% and 99.8%, respectively; P = 0.018) and significantly higher than in patients treated qd (mean qd versus bid: 90% versus 99%, P < 10(-7)). Virus rebounded rapidly upon drug discontinuation, which was attributed to the elimination of active drug and the subsequent decline of drug effectiveness, with mean t(1/2) = 13.9 hours in the bid regimens. CONCLUSION: The observed slower initial decline likely represents the time needed to accumulate intracellular triphosphates and is consistent with in vitro data. When administered bid, mericitabine reached a high, dose-dependent, final effectiveness in blocking viral production that rapidly dropped upon treatment cessation. Understanding HCV RNA kinetics with mericitabine could provide valuable insights for combining it with other direct-acting antiviral agents.
RCT Entities:
UNLABELLED: Mericitabine (RG7128) is a nucleoside polymerase inhibitor (NPI), which requires intracellular uptake and phosphorylation to two active triphosphates. Mathematical modeling has provided important insights for characterizing hepatitis C virus (HCV) RNA decline and estimating in vivo effectiveness of antiviral agents; however, it has not been used to characterize viral kinetics with NPIs. HCV RNA was frequently measured in 32 treatment-experienced patients infected with HCV genotype 1 during and after mericitabine monotherapy for 14 days with 750 mg or 1500 mg administered once (qd) or twice daily (bid). The initial decline of HCV RNA was typically slower than with interferon-α or protease inhibitors, and 12 patients presented a novel pattern of HCV RNA kinetics characterized by a monophasic viral decline. Viral kinetics could be well fitted by assuming that the effectiveness in blocking viral production gradually increased over time to reach its final value, ε(2), consistent with previous accumulation time estimates of intracellular triphosphates. ε(2) was high with bid dosing (mean 750 mg and 1500 mg: 98.0% and 99.8%, respectively; P = 0.018) and significantly higher than in patients treated qd (mean qd versus bid: 90% versus 99%, P < 10(-7)). Virus rebounded rapidly upon drug discontinuation, which was attributed to the elimination of active drug and the subsequent decline of drug effectiveness, with mean t(1/2) = 13.9 hours in the bid regimens. CONCLUSION: The observed slower initial decline likely represents the time needed to accumulate intracellular triphosphates and is consistent with in vitro data. When administered bid, mericitabine reached a high, dose-dependent, final effectiveness in blocking viral production that rapidly dropped upon treatment cessation. Understanding HCV RNA kinetics with mericitabine could provide valuable insights for combining it with other direct-acting antiviral agents.
Authors: Bambang S Adiwijaya; Brian Hare; Paul R Caron; John Cr Randle; Avidan U Neumann; Hendrik W Reesink; Stefan Zeuzem; Eva Herrmann Journal: Antivir Ther Date: 2009
Authors: John G McHutchison; Gregory T Everson; Stuart C Gordon; Ira M Jacobson; Mark Sulkowski; Robert Kauffman; Lindsay McNair; John Alam; Andrew J Muir Journal: N Engl J Med Date: 2009-04-30 Impact factor: 91.245
Authors: Harel Dahari; Jennifer E Layden-Almer; Eric Kallwitz; Ruy M Ribeiro; Scott J Cotler; Thomas J Layden; Alan S Perelson Journal: Gastroenterology Date: 2009-01-01 Impact factor: 22.682
Authors: Han Ma; Wen-Rong Jiang; Nicole Robledo; Vincent Leveque; Samir Ali; Teresa Lara-Jaime; Mohammad Masjedizadeh; David B Smith; Nick Cammack; Klaus Klumpp; Julian Symons Journal: J Biol Chem Date: 2007-08-13 Impact factor: 5.157
Authors: Markus M Knodel; Paul Targett-Adams; Alfio Grillo; Eva Herrmann; Gabriel Wittum Journal: Int J Environ Res Public Health Date: 2019-02-12 Impact factor: 3.390
Authors: Markus M Knodel; Sebastian Reiter; Paul Targett-Adams; Alfio Grillo; Eva Herrmann; Gabriel Wittum Journal: Viruses Date: 2017-09-30 Impact factor: 5.048