title: Maximum a posteriori Bayesian estimation of oral cyclosporin pharmacokinetics in patients with stable renal transplants.
abstract: OBJECTIVE
  To develop a maximum a posteriori probability (MAP) Bayesian estimator for the pharmacokinetics of oral cyclosporin, based on only three timepoints, and evaluate its performance with respect to a full-profile nonlinear regression approach.
  
  
  METHODS
  20 adult patients with stable renal transplants given orally administered microemulsified cyclosporin and mycophenolate.
  
  
  METHODS
  Cyclosporin was assayed by liquid chromatography-mass spectrometry. Nonlinear regression and MAP Bayesian estimation were performed using a home-made program and a previously designed pharmacokinetic model including an S-shaped absorption profile described by a gamma distribution.
  
  
  RESULTS
  MAP Bayesian estimation using the best limited sampling strategy (before administration, and 1 and 3 hours after administration) was compared with nonlinear regression (taken as the reference method) for the prediction of the different pharmacokinetic parameters and exposure indices. Median relative prediction error was -0.49 and -3.42% for area under the concentration-time curve over the administration interval of 12 hours (AUC12) and estimated peak drug concentration (Cmax), respectively (nonsignificant). Relative precision was 2.00 and 4.32%, and correlation coefficient (r) was 0.985 and 0.955, for AUC12 and Cmax, respectively.
  
  
  CONCLUSIONS
  This paper reports preliminary results in a stable renal transplant patient population, showing that MAP Bayesian estimation can allow accurate prediction of AUC12 and Cmax with only three samples (0, 1 and 3 hours). Although these results require confirmation by further studies in other clinical settings, using other drug combinations, other analytical methods and commercially available pharmacokinetic software, the method seems promising as a tool for the therapeutic drug monitoring of cyclosporin in clinical practice or for exposure-controlled studies.
authors.affiliation: Service de Pharmacologie et Toxicologie, CHU Dupuytren, Limoges, France. marquet@unilim.fr
authors.forename: Frédéric
authors.initials: F
authors.lastname: Leger
authors.forename: Jean
authors.initials: J
authors.lastname: Debord
authors.forename: Yann
authors.initials: Y
authors.lastname: Le Meur
authors.forename: Annick
authors.initials: A
authors.lastname: Rousseau
authors.forename: Mathias
authors.initials: M
authors.lastname: Büchler
authors.forename: Gérard
authors.initials: G
authors.lastname: Lachâtre
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001499:Bayes Theorem; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004655:Emulsions; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D016013:Likelihood Functions; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D017711:Nonlinear Dynamics
chemical_list: D004655:Emulsions; D007166:Immunosuppressive Agents; D016572:Cyclosporine