Population Pharmacokinetics of Mycophenolic Acid in Kidney Transplant Pediatric and Adolescent Patients

Abstract

Current data on mycophenolate mofetil (MMF) suggest that there is a pharmacokinetic/pharmacodynamic relationship between the mycophenolic acid (MPA) area under the curve (AUC) during treatment and both the risk of acute rejection and the occurrence of side effects. The aim of this study was to characterize the population pharmacokinetics of MPA in kidney transplant patients between the ages of 2 and 21 years and to propose a limited sampling strategy to estimate individual MPA AUCs. Forty-one patients received long-term oral MMF continuous therapy as part of a triple immunosuppressive regimen, which also included cyclosporine or tacrolimus (n=3) and corticosteroids. Therapy was initiated at a dose of 600 mg/m twice daily. The population parameters were calculated from an initial group of 32 patients. The data were analyzed by nonlinear mixed-effect modeling using a 2-compartment structural model with first-order absorption and a lag time. The interindividual variability in the initial volume of distribution was partially explained by the fact that this parameter was weight-dependent. Fifteen concentration-time profiles from 13 patients were used to evaluate the predictive performance of the Bayesian approach and to devise a limited sampling strategy. The protocol, involving two sampling times, 1 and 4 hours after oral administration, allows the precise and accurate determination of MPA AUCs (bias -0.9 microg.h/mL; precision 6.02 microg.h/mL). The results of this study combine the relationships between the pharmacokinetic parameters of MPA and patient covariates, which may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing pediatric patient care.

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

“…Blood samples were collected in tubes containing ethylenediaminetetraacetate (EDTA), immediately centrifuged, and kept frozen (−20°C) until centralized analysis. Plasma MPA concentrations were determined by high-performance liquid chromatography (HPLC) with ultraviolet detection using method previously used in our laboratory [23]. PK parameters were normally distributed (tested by Kolmogorov-Smirnov test) and are expressed as mean ± SD.…”

Development of a CE method for the determination of mycophenolic acid in human plasma: A comparison with HPLC

“…The current success of organ transplantation is largely correlated to advances in immunosuppressive therapy and very few allografts are now lost as a result of acute rejection. Mycophenolate mofetil (MMF) has become in recent years a more widely prescribed drug, used for maintenance immunosuppressive therapy both in adult [1] and pediatric renal-transplant recipients [2].…”

Comparison of high-performance liquid chromatography and enzyme-multiplied immunoassay technique to monitor mycophenolic acid in paediatric renal recipients

“…However, pharmacokinetics studies in adults and children revealed substantial inter-and intra-individual variability in pharmacokinetics parameters, and significant drug interactions [3,[10][11][12][13]. Therefore, both in adults and children, TDM of MPA is now an important tool in transplantation to optimize therapy [13][14][15].…”