Maximum a posteriori Bayesian estimation of oral cyclosporin pharmacokinetics in patients with stable renal transplants.
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.
Leger
Frédéric
F
Service de Pharmacologie et Toxicologie, CHU Dupuytren, Limoges, France. marquet@unilim.fr
Debord
Jean
J
Le Meur
Yann
Y
Rousseau
Annick
A
Büchler
Mathias
M
Lachâtre
Gérard
G
Paintaud
Gilles
G
Marquet
Pierre
P
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
D004655:Emulsions; D007166:Immunosuppressive Agents; D016572:Cyclosporine