title: Inotropic effect of digoxin in humans: mechanistic pharmacokinetic/pharmacodynamic model based on slow receptor binding.
abstract: OBJECTIVE
  The purpose of this study was to construct a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for digoxin that describes the relationship between plasma concentration and inotropic response.
  
  
  METHODS
  On the basis of results obtained in the isolated perfused rat heart, a PK/PD model for digoxin in humans was developed. In fitting the model to previously published bolus dose and concentration clamp data (shortening of electromechanical systole), the plasma concentration-time curves were used as forcing functions in the computer program ADAPT II.
  
  
  RESULTS
  The mechanistic approach allowed a modeling of digoxin pharmacodynamics which is consistent with available inotropic response data. The estimates of the receptor binding parameters were in the same order of magnitude as those measured in vitro for ouabain. The mechanistic model explained the parameters of the empirical link model (EC50, Emax and delay time tau) in terms of the underlying processes, suggesting that the long equilibration half-time of 13 h is due to slow receptor binding. The empirical link model, in contrast, is not compatible with a noninstantaneous receptor binding process and led to estimates of the delay time tau that were dependent on the digoxin administration schedule.
  
  
  CONCLUSIONS
  The new, mechanistic model may provide a rationale for better understanding of digoxin pharmacodynamics and could become a tool to bridge the gap between in vitro and in vivo studies.
authors.affiliation: Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany. michael.weiss@medizin.uni-halle.de
authors.forename: Michael
authors.initials: M
authors.lastname: Weiss
authors.forename: Wonku
authors.initials: W
authors.lastname: Kang
mesh_terms: D000818:Animals; D001665:Binding Sites; D002316:Cardiotonic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013997:Time Factors
chemical_list: D002316:Cardiotonic Agents; D020033:Protein Isoforms; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase