Consensus Report on Therapeutic Drug Monitoring of Mycophenolic Acid in Solid Organ Transplantation

Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
Clinical Journal of the American Society of Nephrology (Impact Factor: 4.61). 02/2010; 5(2):341-58. DOI: 10.2215/CJN.07111009
Source: PubMed


With the increasing use of mycophenolic acid (MPA) in solid organ transplantation, the need for more accurate drug dosing has become evident. Personalized immunosuppressive therapy requires better strategies for avoidance of drug-related toxicity while maintaining efficacy. Few studies have assessed the clinical usefulness of therapeutic drug monitoring (TDM) of MPA in solid organ transplantation in a prospective way, and they have produced opposing results. To provide clinicians with an objective and balanced clinical interpretation of the current scientific evidence on TDM of MPA, a consensus meeting involving 47 experts from around the world was commissioned by The Transplantation Society and held in Rome on November 20 to 21, 2008. The goal of this consensus meeting was to offer information to transplant practitioners on clinically relevant pharmacokinetic characteristics of MPA, to rationalize the basis for currently advised target exposure ranges for MPA in various types of organ transplantation, and to summarize available methods for application of MPA TDM in clinical practice. Although this consensus report does not evaluate the final role of MPA TDM in transplantation, it seeks to examine the current scientific evidence for concentration-controlled dosing of MPA.

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    • "In heart transplantation, it is recommended to initiate the treatment with a 1.5 g bid dose of MMF [4]. As for other types of transplantations, such a fixed-dose cannot ensure a reliable exposure to MPA in all patients, implying that MMF dose adjustment might be beneficial. "
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    ABSTRACT: Mycophenolic acid (MPA) area under the curve (AUC) has been associated with graft outcome. (1) to develop pharmacokinetic tools to optimize MPA inter-dose AUC estimation in heart transplant patients; and (2) to investigate the relationships between acute allograft rejection and MPA AUC, trough level (C0) or mycophenolate mofetil (MMF) dose. Two independent modeling approaches (parametric and non parametric) were used to fit 56 rich MPA pharmacokinetic (PK) profiles collected from 40 adult heart transplant recipients enrolled in the PIGREC study, receiving MMF and a calcineurin inhibitor (CNI), in the first year post-transplantation. In addition, associations between drug exposure (MPA C0, AUC and MMF dose) and acute rejection or MMF adverse events were investigated using time-dependent Cox models with stratification on the type of calcineurin inhibitor. Exposure threshold values were investigated using ROC curve analysis. The 2 models developed fit adequately the data and the use of their combination yielded 100% consistency with the measured AUC in terms of strategy of dose adjustment (maintain, increase or decrease). MPA measured AUC adjusted on CNI exposure was significantly associated with rejection (per unit increase: HR [95% CI]=0.97 [0.95-0.99], p=0.0122), while no effect was shown for adverse events attributable to MMF. An AUC threshold of 50mg×h/L was proposed (sensitivity=77%, specificity=25%) beyond which the risk of rejection was significantly increased (low vs. high: HR=3.48 [1.21-10.0], p=0.0204). The tools developed have already been made available to the heart transplant community on our ISBA website ( Copyright © 2015. Published by Elsevier Ltd.
    Pharmacological Research 07/2015; 99. DOI:10.1016/j.phrs.2015.07.012 · 4.41 Impact Factor
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    • "Current trends towards personalized immunosuppressive therapy require better strategies for avoidance of drug-related toxicity while maintaining efficacy [57]–[59]. In our previous studies, we had shown that one of the reasons for the enhancement of CsA toxicity by SRL may be a toxicokinetic interaction leading to increased CsA kidney tissue concentrations in the presence of SRL [20], [60]. "
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    ABSTRACT: Mycophenolate mofetil (MMF) per se is not known to have negative effects on the kidney. MMF alone or in combination with sirolimus, can be the basis of calcineurin inhibitor (CNI)-free, kidney sparing drug protocols. However, long-term outcomes in patients on MMF/SRL seem to be inferior to those treated with regimens that include the CNI tacrolimus (TAC) due to an increased risk of allo-immune reactions. Interestingly, potential enhancement of the negative effects of SRL and TAC on the kidney by MMF has never been considered. It was our aim to study the effects of TAC, SRL and MMF alone and evaluate their interactions when combined on the rat kidney. For this purpose we used a comprehensive molecular marker approach including measurements of urinary 8-isoprostane concentrations (oxidative stress marker) and changes of urinary metabolite patterns ((1)H-NMR spectroscopy) and comparing these markers to renal function (glomerular filtration rate (GFR)) and morphologic alterations (histology). While MMF alone did not impact GFR, its interaction with SRL and TAC led to a significant decrease of rats' renal function. The decline went in parallel with a significant increase in urinary isoprostane concentrations and an enhancement of negative effects on urinary metabolite patterns. In broad summary, the present study showed that MMF may enhance the negative effects of TAC on kidney function and may even display nephrotoxic properties when combined with SRL.
    PLoS ONE 01/2014; 9(1):e86202. DOI:10.1371/journal.pone.0086202 · 3.23 Impact Factor
    • "In heart transplantation, it is recommended to initiate the treatment with a 1.5 g bid dose of MMF [4]. As for other types of transplantations, such a fixed-dose cannot ensure a reliable exposure to MPA in all patients, implying that MMF dose adjustment might be beneficial. "
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    ABSTRACT: Mycophenolic acid (MPA) area under the curve (AUC) has been reported as an important marker of graft outcome. The aim of our study was to develop: (i) population pharmacokinetic (POPPK) models in adult heart transplant patients using a parametric (P) and a nonparametric (NP) approach; and (ii) two independent Bayesian estimators (BE) enabling AUC determination using a limited sampling strategy.Methods and MaterialsFifty-six MPA pharmacokinetic (PK) profiles were collected from 39 adult heart transplant patients given mycophenolate mofetil. POPPK analysis was performed using both the parametric iterative two-stage Bayesian method and the nonparametric adaptive grid approach (using Pmetrics R package). The PK profiles were fitted to a one-compartment model with first-order elimination combined to two gamma laws to describe the absorption phase.ResultsPK profiles were divided into a development dataset (n=37) and a validation dataset (n=19). For each approach, a POPPK model was developed that accurately fitted the observed data. In the validation group, the BE developed using each model yielded good AUC estimation performance (bias of -1.26±19.33% (P) and -1.12±19.34% (NP)) on the basis of a 20, 60, 180 and 360 minutes sampling schedule. Accordingly, dose adjustment (for a 45 mg.h/L target AUC) based on BE was similar to that proposed on the basis of the reference AUC (trapezoidal AUC using all the available concentrations) in 79% (P) and 84% (NP) of the patients.Conclusions The PK profiles of MPA in heart transplant patients are more complex than those observed in kidney graft recipients. Bayesian estimators allowing the determination of MPA AUC using a limited number of blood samples have been developed using 2 totally independent population modelling approaches, the combination of which now increase the accuracy of our results. They are now available on our ISBA website ( for routine dose adjustment.
    The Journal of Heart and Lung Transplantation 04/2013; 32(4):S111. DOI:10.1016/j.healun.2013.01.230 · 6.65 Impact Factor
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