title: A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV.
abstract: BACKGROUND
  Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct-acting antivirals.
  
  
  METHODS
  We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a Phase I study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naive and 8 were non-responders to prior pegylated IFN-α/ribavirin treatment.
  
  
  RESULTS
  In all patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VK model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. The antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg twice daily) and 0.99 at the highest dose (200 mg three times daily). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg twice daily). The second phase decline showed two different behaviours, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 day(-1)), whereas the viral decline was slower in the other patients.
  
  
  CONCLUSIONS
  Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Canini
authors.forename: Anushree
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Jeremie
authors.initials: J
authors.lastname: Guedj
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lemenuel-Diot
authors.forename: Barbara
authors.initials: B
authors.lastname: Brennan
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
mesh_terms: D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003521:Cyclopropanes; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D054833:Isoindoles; D007769:Lactams / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic; D008962:Models, Theoretical; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D003841:Deoxycytidine; D016898:Interferon-alpha; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011092:Polyethylene Glycols; D011392:Proline; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D012254:Ribavirin; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; C553752:danoprevir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C100416:peginterferon alfa-2a