title: Modelling clinical data shows active tissue concentration of daclatasvir is 10-fold lower than its plasma concentration.
abstract: OBJECTIVE
  Daclatasvir is a highly potent inhibitor of hepatitis C virus. We estimated the active tissue concentration of daclatasvir in vivo.
  
  
  METHODS
  We developed a mathematical model incorporating pharmacokinetic/pharmacodynamic and viral dynamics. By fitting the model to clinical data reported previously, we estimated the ratio between plasma drug concentration and active tissue concentration in vivo.
  
  
  RESULTS
  The modelling results show that the active tissue concentration of daclatasvir is ∼9% of the concentration measured in plasma (95% CI 1%-29%).
  
  
  CONCLUSIONS
  Using plasma concentrations as surrogates for clinical recommendations may lead to substantial underestimation of the risk of resistance.
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Ruian
authors.initials: R
authors.lastname: Ke
authors.forename: Claude
authors.initials: C
authors.lastname: Loverdo
authors.forename: Hangfei
authors.initials: H
authors.lastname: Qi
authors.forename: C Anders
authors.initials: CA
authors.lastname: Olson
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Wu
authors.forename: Ren
authors.initials: R
authors.lastname: Sun
authors.forename: James O
authors.initials: JO
authors.lastname: Lloyd-Smith
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002219:Carbamates; D002986:Clinical Trials as Topic; D016174:Hepacivirus / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008962:Models, Theoretical; D010949:Plasma / Q000737:chemistry*; D011759:Pyrrolidines; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D014633:Valine; C549273:daclatasvir
keywords: hepatitis C virus; mathematical modeling; pharmacokinetics/pharmacodynamics; resistance