Bayesian estimation of cyclosporin exposure for routine therapeutic drug monitoring in kidney transplant patients.
OBJECTIVE
AUC-based monitoring of cyclosporin A (CsA) is useful to optimize dose adaptation in difficult cases. We developed a population pharmacokinetic model to describe dose-exposure relationships for CsA in renal transplant patients and applied it to the Bayesian estimation of AUCs using three blood concentrations.


METHODS
A total of 84 renal graft recipients treated with CsA microemulsion were included in this study. Population pharmacokinetic analysis was conducted using NONMEM. A two-compartment model with zero-order absorption and a lag time best described the data. Bayesian estimation was based on CsA blood concentrations measured before dosing and 1 h and 2 h post dose. Predictive performance was evaluated using a cross-validation approach. Estimated AUCs were compared with AUCs calculated by the trapezoidal method. The Bayesian approach was also applied to an independent group of eight patients exhibiting unusual pharmacokinetic profiles.


RESULTS
Mean population pharmacokinetic parameters were apparent clearance 30 l h(-1), apparent volume of distribution 79.8 l, duration of absorption 52 min, absorption lag time 7 min. No significant relationships were found between any of the pharmacokinetic parameters and individual characteristics. A good correlation was obtained between Bayesian-estimated and experimental AUCs, with a mean prediction error of 2.8% (95% CI [-0.6, 6.2]) and an accuracy of 13.1% (95% CI [7.5, 17.2]). A good correlation was also obtained in the eight patients with unusual pharmacokinetic profiles (r(2) = 0.96, P < 0.01).


CONCLUSIONS
Our Bayesian approach enabled a good estimation of CsA exposure in a population of patients with variable pharmacokinetic profiles, showing its usefulness for routine AUC-based therapeutic drug monitoring.
Bourgoin
Hélène
H
Department of Pharmacology, University Hospital of Tours, 2 boulevard Tonnellé, 37044 Tours cedex 9, France.
Paintaud
Gilles
G
Büchler
Matthias
M
Lebranchu
Yvon
Y
Autret-Leca
Elisabeth
E
Mentré
France
F
Le Guellec
Chantal
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001499:Bayes Theorem; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
D007166:Immunosuppressive Agents; D016572:Cyclosporine