title: A Prediction Model of Drug Exposure in Cirrhotic Patients According to Child-Pugh Classification.
abstract: OBJECTIVE
  Prediction of drug clearance in liver cirrhosis patients is currently based on in vitro-in vivo extrapolation and physiologically-based pharmacokinetic models. No static model for this purpose has been described. The objectives of this study were to (1) derive a static model for predicting drug exposure in cirrhotic patients, and (2) to evaluate the model on a large set of published data.
  
  
  METHODS
  The impact of cirrhosis was characterized by the ratio of the total and unbound drug area under the concentration-time curve (AUC) in cirrhotic patients to the AUC measured in healthy subjects These ratios were predicted for Child-Pugh classes A, B, and C. The AUC ratios observed in published data were compared with AUC ratios predicted by the model.
  
  
  RESULTS
  Among 171 drugs examined, 83 published AUC ratios for 45 drugs in cirrhotic patients were available for analysis. The mean ± standard deviation relative prediction error for the total and unbound AUC ratios was 0.22 ± 0.58 and 0.24 ± 0.56, respectively. There were four outliers among the 83 predicted values. Simulations showed that the prediction error was negligible provided that the hepatic extraction coefficient was less than 0.8.
  
  
  CONCLUSIONS
  For mild and moderate cirrhosis (classes A and B), the predicted unbound AUC ratio is typically approximately 2 and 3.5, respectively, for most drugs. In the absence of data in cirrhotic patients, the drug dose might be empirically reduced by these factors. In severe cirrhosis (class C), our model may help clinicians to adjust their prescriptions.
authors.affiliation: Pharmacie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 103 Grande Rue de la Croix-Rousse, 69004, Lyon, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Steelandt
authors.affiliation: Pharmacie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 103 Grande Rue de la Croix-Rousse, 69004, Lyon, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Jean-Bart
authors.affiliation: Pharmacie, Hôpital Pierre Garaud, Hospices Civils de Lyon, Lyon, France.|UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Université Lyon 1, Villeurbanne, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Goutelle
authors.affiliation: Pharmacie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 103 Grande Rue de la Croix-Rousse, 69004, Lyon, France. michel.tod@univ-lyon1.fr.|Département de Physiologie, Pharmacologie, Toxicologie, Faculté de Pharmacie, Université Lyon 1, Lyon, France. michel.tod@univ-lyon1.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Tod
mesh_terms: D019540:Area Under Curve; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010599:Pharmacokinetics; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests
chemical_list: D003577:Cytochrome P-450 Enzyme System