title: Use of modelling and simulation techniques to support decision making on the progression of PF-04878691, a TLR7 agonist being developed for hepatitis C.
abstract: OBJECTIVE
  To use non-linear mixed effects modelling and simulation techniques to predict whether PF-04878691, a toll-like receptor 7 (TLR7) agonist, would produce sufficient antiviral efficacy while maintaining an acceptable side effect profile in a 'proof of concept' (POC) study in chronic hepatitis C (HCV) patients.
  
  
  METHODS
  A population pharmacokinetic-pharmacodynamic (PKPD) model was developed using available 'proof of pharmacology' (POP) clinical data to describe PF-04878691 pharmacokinetics (PK) and its relationship to 2',5'-oligoadenylate synthetase (OAS; marker of pharmacology) and lymphocyte levels (marker of safety) following multiple doses in healthy subjects. A second model was developed to describe the relationship between change from baseline OAS expressed as fold change and HCV viral RNA concentrations using clinical data available in HCV patients for a separate compound, CPG-10101 (ACTILON™), a TLR9 agonist. Using these models the antiviral efficacy and safety profiles of PF-04878691 were predicted in HCV patients.
  
  
  RESULTS
  The population PKPD models described well the clinical data as assessed by visual inspection of diagnostic plots, visual predictive checks and precision of the parameter estimates. Using these relationships, PF-04878691 exposure and HCV viral RNA concentration was simulated in HCV patients receiving twice weekly administration for 4 weeks over a range of doses. The simulations indicated that significant reductions in HCV viral RNA concentrations would be expected at doses > 6 mg. However at these doses grade ≥ 3 lymphopenia was also predicted.
  
  
  CONCLUSIONS
  The model simulations indicate that PF-04878691 is unlikely to achieve POC criteria and support the discontinuation of this compound for the treatment of HCV.
authors.affiliation: Pfizer Worldwide R&D, Department of Pharmacokinetics, Dynamics and Metabolism, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. Hannah.jones@pfizer.com
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.forename: Phylinda L S
authors.initials: PL
authors.lastname: Chan
authors.forename: Piet H
authors.initials: PH
authors.lastname: van der Graaf
authors.forename: Robert
authors.initials: R
authors.lastname: Webster
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000493:pharmacokinetics*; D000328:Adult; D003198:Computer Simulation; D003661:Decision Support Techniques; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016032:Randomized Controlled Trials as Topic; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D019562:Viral Load / Q000187:drug effects*; D055815:Young Adult
chemical_list: D051199:Toll-Like Receptor 7; D015088:2',5'-Oligoadenylate Synthetase