title: Hepatitis C viral kinetics with the nucleoside polymerase inhibitor mericitabine (RG7128).
abstract: 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.
  
  
  CONCLUSIONS
  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.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Guedj
authors.forename: Harel
authors.initials: H
authors.lastname: Dahari
authors.forename: Emi
authors.initials: E
authors.lastname: Shudo
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D054306:Dideoxynucleotides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy / Q000378:metabolism / Q000821:virology*; D006801:Humans; D008962:Models, Theoretical; D012367:RNA, Viral / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects* / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology*
chemical_list: C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; D000998:Antiviral Agents; D054306:Dideoxynucleotides; D004791:Enzyme Inhibitors; D012367:RNA, Viral; D003841:Deoxycytidine
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