Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantation

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS PROJECT? • Mycophenolate mofetil (MMF) is an immunosuppressant drug used for the treatment and prevention of graft vs. host disease in blood or marrow transplantation and acute graft rejection in solid organ transplantation. • Mycophenolic acid (MPA) pharmacokinetics have not been thoroughly studied in paediatric blood or marrow transplant recipients and guidance for optimal dosing of mycophenolic acid in children is lacking. • Mycophenolic acid exhibits considerable inter‐ and intra‐patient pharmacokinetic variability in adults and paediatric transplant recipients. • The AUC of mycophenolic acid over a 12 h dose interval at steady‐state is generally agreed to be the most reliable metric associated with the risk of acute rejection. • Population pharmacokinetic analysis can utilize concentration information from both intensive sampling and sparse sampling to provide pharmacokinetic parameter estimates, estimates of inter‐ individual and intra‐individual variability in these parameters and allows patient characteristics explaining inter‐individual variability to be quantified. WHAT THIS STUDY ADDS • This study is one of the first investigations in which a population pharmacokinetic modelling approach was applied to assess the pharmacokinetics of both intravenous and oral MMF in children and young people undergoing blood or marrow and solid organ transplantation. • Bodyweight and concomitant ciclosporin were found to influence MPA pharmacokinetics. • This study evaluated current dosing strategies and found that they may be suboptimal for children weighing less than 10 kg. AIMS To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. METHODS MPA concentration–time data were collected using an age specific sampling protocol over 12 h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12 h) within the range 30 and 60 mg l−1 h associated with optimal outcome. RESULTS A two‐compartment pharmacokinetic model with first‐order elimination best described MPA concentration–time data. Population mean estimates of MPA clearance, inter‐compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h−1, 3.74 l h−1, 7.24 l, 16.8 l, 0.39 h−1 and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter‐individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10 kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. CONCL...

A multiple methods approach to determine adherence with prescribed mycophenolate in children with kidney transplant

“…Assessing adherence to mycophenolate after transplant using plasma MPA concentration has been reported in the literature; however, in the present study assessment of patient adherence using this approach also involved PopPK modelling, adding to the robustness of the technique. Published research on the PopPK of MPA in children has been reported previously . The clearance model developed by Zeng et al (2010) was selected as the most suitable model for the use in the present population of children as the latter model includes concomitant use of cyclosporine or tacrolimus as covariates.…”

“…Published research on the PopPK of MPA in children has been reported previously . The clearance model developed by Zeng et al (2010) was selected as the most suitable model for the use in the present population of children as the latter model includes concomitant use of cyclosporine or tacrolimus as covariates. The results also illustrated the utility of using the DBS sampling approach to assess adherence to mycophenolate, i.e.…”

“…To determine whether a child was adherent, a computer simulation method was utilised to estimate the 95% interval of predicted plasma concentrations for MPA at the time of sampling relative to time of dose administration ( n = 1000 sets of simulations using the nonlinear mixed effect modelling software package, NONMEM version 7.3.0; Icon Development Solutions, Ellicott City, MD, USA). In this approach, literature values of PopPK parameters for MPA were employed . In addition, significant covariates reported to influence PK parameters (e.g.…”

Testing new drugs in naked apes and getting the dose right in their young

“…As a result, the same dose kg −1 does not result in the same circulating concentration because the absorption/metabolism/clearance is different.’ Two further papers in the current issue support relatively straightforward approaches. Zeng and colleagues studied the population pharmacokinetics of mycophenolic acid in children undergoing marrow and solid organ transplantation [13]. Body weight and concomitant ciclosporin treatment influenced the pharmacokinetics, and current dosing strategies may be suboptimal for children weighing <10 kg.…”

The Application of Inosine 5′-Monophosphate Dehydrogenase Activity Determination in Peripheral Blood Mononuclear Cells for Monitoring Mycophenolate Mofetil Therapy in Children with Nephrotic Syndrome

“…Significant inter- and intrapatient variability of MPA pharmacokinetics provides the basis for therapeutic drug monitoring (TDM) in the case of MMF; however, its importance is still being discussed [ 1 ]. In the literature, studies of MPA pharmacokinetics concern mainly children after transplantation [ 7 , 8 , 9 , 10 , 11 ]. However, in our previous study [ 12 ], in children with nephrotic syndrome, we observed higher trough MPA concentration (C trough ) and area under the time-concentration curve (AUC) if compared to recommended C trough and AUC for transplant recipients [ 8 ].…”