Population pharmacokinetics and Bayesian estimator of mycophenolic acid in children with idiopathic nephrotic syndrome.
OBJECTIVE
To develop a population pharmacokinetic model for mycophenolic acid (MPA) in children with idiopathic nephrotic syndrome (INS) treated with mycophenolate mofetil (MMF), identify covariates that explain variability and determine the Bayesian estimator of the area under the concentration-time curve over 12 h (AUC(0-12)).


METHODS
The pharmacokinetic model of MMF was described from 23 patients aged 7.4 +/- 3.9 years (range 2.9-14.9) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with lag-time and first-order absorption and elimination was developed. The final model was validated using visual predictive check. Bayesian estimator was validated using circular permutation method.


RESULTS
The population pharmacokinetic parameters were apparent oral clearance 9.7 l h(-1), apparent central volume of distribution 22.3 l, apparent peripheral volume of distribution 250 l, inter-compartment clearance 18.8 l h(-1), absorption rate constant 5.16 h(-1), lag time 0.215 h. The covariate analysis identified body weight and serum albumin as individual factors influencing the apparent oral clearance. Accurate Bayesian estimation of AUC(0-12) was obtained using the combination of three MPA concentrations measured just before (T(0)), 1 and 4 h (T(1) and T(4)) after drug intake with a small error of 0.298 microg h(-1) ml(-1) between estimated and reference AUC(0-12).


CONCLUSIONS
The population pharmacokinetic model of MPA was developed in children with INS. A three-point (T(0), T(1) and T(4)h) Bayesian estimator of AUC(0-12) was developed and might be used to investigate the relation between MPA pharmacokinetic and pharmacodynamics in children with INS and determine if there is any indication to monitor MPA exposure in order to improve patient outcome based on individual AUC-controlled MMF dosing.
Zhao
Wei
W
Department of Paediatric Pharmacology and Pharmacogenetics, Clinical Investigation Centre INSERM, Hôpital Robert Debré, Paris, France.
Elie
Valéry
V
Baudouin
Véronique
V
Bensman
Albert
A
André
Jean Luc
JL
Brochard
Karine
K
Broux
Françoise
F
Cailliez
Mathilde
M
Loirat
Chantal
C
Jacqz-Aigrain
Evelyne
E
D000284:Administration, Oral; D000293:Adolescent; D019540:Area Under Curve; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009404:Nephrotic Syndrome / Q000188:drug therapy*; D011446:Prospective Studies
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid
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