title: A pharmacokinetic approach for evaluating cytokine binding macromolecules as antagonists.
abstract: OBJECTIVE
  Cytokine binding macromolecules such as antibodies and soluble receptors sometimes produce undesirable agonist-like activities instead of the expected antagonist-like effects when the cytokine binding macromolecule extends the half-life of a short-lived cytokine. The purpose of this paper is to identify the pharmacokinetic and physicochemical properties that can cause these agonist-like activities.
  
  
  METHODS
  A simple pharmacokinetic model was used to determine whether a given cytokine binding macromolecule will function effectively as an antagonist in therapeutic situations in which cytokine is released chronically.
  
  
  RESULTS
  The model proposed satisfactorily fits experimental data for soluble interleukin-4 receptor and for an anti-interleukin-4 monoclonal antibody under conditions in which agonist-like and antagonist activity are observed.
  
  
  CONCLUSIONS
  We show that the unexpected agonist-like activities result only when there is nonlinearity in the cytokine-cytokine receptor interaction and the cytokine binding macromolecule prolongs the half-life of the cytokine.
authors.affiliation: Department of Pharmaceutics, State University of New York at Buffalo 14260-1200, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ramanathan
mesh_terms: D055598:Chemical Phenomena; D002627:Chemistry, Physical; D016207:Cytokines / Q000378:metabolism / Q000493:pharmacokinetics*; D005069:Evaluation Studies as Topic; D006207:Half-Life; D015847:Interleukin-4 / Q000378:metabolism*; D008954:Models, Biological; D018121:Receptors, Cytokine / Q000819:agonists / Q000037:antagonists & inhibitors*
chemical_list: D016207:Cytokines; D018121:Receptors, Cytokine; D015847:Interleukin-4