Population pharmacokinetics and Bayesian estimator of mycophenolic acid in children with idiopathic nephrotic syndrome

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• MMF has been proposed as a treatment of steroid-dependent nephrotic syndrome and in the recent years, several studies have suggested its positive effect in preventing relapses. WHAT THIS PAPER ADDS• The population pharmacokinetics of MPA was first evaluated in children with idiopathic nephrotic syndrome and data fitted well with a two-compartment model with first-order absorption and lag time.• Body weight and serum albumin had a significant impact on oral clearance. • A three-point (T0, T1 and T4h) Bayesian estimator of AUC0-12 was developed. AIMSTo 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 (AUC0-12). METHODSThe pharmacokinetic model of MMF was described from 23 patients aged 7.4 Ϯ 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. RESULTSThe population pharmacokinetic parameters were apparent oral clearance 9.7 l h , 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 AUC0-12 was obtained using the combination of three MPA concentrations measured just before (T0), 1 and 4 h (T1 and T4) after drug intake with a small error of 0.298 mg h -1 ml -1 between estimated and reference AUC0-12. CONCLUSIONSThe population pharmacokinetic model of MPA was developed in children with INS. A three-point (T0, T1 and T4h) Bayesian estimator of AUC0-12 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.

Monitoring of mycophenolate mofetil metabolites in children with nephrotic syndrome and the proposed novel target values of pharmacokinetic parameters

“…Median as well as mean dose-normalized MPA AUC 12 (44.7 lg h/mL ± 24.9 lg h/mL) obtained in our study were comparable to the literature data concerning children with nephrotic syndrome (Zhao et al, 2010;Baudouin et al, 2012), in stable period after renal transplantation (Weber et al, 2008) or in liver transplant recipients (Barau et al, 2011;Lobritto et al, 2007). In our study, dose-normalized MPA AUC 12 was lower in children with proteinuria, however, it was not statistically significant and proteinuria was observed also in the child with one of the highest MPA AUC 12 .…”

“…Additionally, the variability of MMF metabolites pharmacokinetics in children may be affected by various factors (treatment duration, therapeutic indication, drugs co-administered, genetic, physiological and environmental factors as well as kidney or liver dysfunction) (Filler, 2007(Filler, , 2006Parant et al, 2009;Brown et al, 2002;Jacobson et al, 2008;Ghio et al, 2009). There is little data in the literature on the pharmacokinetics of MMF metabolites in children (Filler, 2007(Filler, , 2006, especially diagnosed with nephrotic syndrome (Zhao et al, 2010;Saint-Marcoux et al, 2011). Additionally, food intake may be one of the factors influencing MMF pharmacokinetics.…”

Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial

“…Dorresteijn et al, in children with SDNS, also reported low MPA AUC (27 mg*h/L) in one child who had three relapses within 6 months on MMF, whereas six children with AUC between 40 and 99 mg*h/L had no relapses [18]. Additional studies in pediatric patients with [31,32]. The frequency of adverse effects in our patients was similar to those reported in studies using the same MMF dosage.…”

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV‐infected infants and toddlers

“…From a practical point of view, we stated a priori that the best MAP Bayesian estimator should be selected within 3-4 h post dose (in order to limit outpatients' stay) and the number of samplings should not exceed three [17,18].The selection of the different time points was based on their respective prediction performance.…”

“…Owing to the limited number of patients in this study, the cross-validation method was used to evaluate MAP Bayesian estimator [17]. The full data set was randomly divided into three subsets (each one contains one-third of the pharmacokinetic profiles).…”