Therapeutic drug monitoring of mycophenolates in kidney transplantation: report of The Transplantation Society consensus meeting
Section snippets
Relationship between MPA exposure and efficacy
Numerous studies suggested a relationship between MPA exposure and the risk of acute rejection (reviewed in [2]) in patients treated with MMF. Most studies have addressed patients' coadministered calcineurin inhibitors (CNI) in the first year after transplantation. A paucity of data exists for mamallian target of rapamycin inhibitor–based regimens [3] or those omitting or withdrawing CNI (see below). In addition, the relationship between MPA exposure and efficacy/safety in recipients treated
Relationship between MPA exposure and toxicity
Adverse events likely related to the mycophenolates include gastrointestinal disturbance, hematologic disorders (leukopenia and anemia), and infections (mainly viral infections). The relationship between MPA exposure and these adverse events is weak and somewhat contradictory. In 125 kidney recipients coadministered tacrolimus, a multivariate analysis studying the effect of 1 mg/mL rise in median “total” MPA trough level in the 30 days before the event showed an increased risk of anemia
Inter patient variability of MPA exposure
The pharmacokinetics of MPA are characterized by a high interpatient variability and a time-dependant change [27].
Indeed, patients receiving 1 g twice a day of MMF experience a 10-fold variation in MPA exposure (MPA AUC) [28]. The second PK characteristic to take into account is the increase of dose-corrected MPA exposure over time. A 40% to 50% increase in MPA exposure at a steady dose of drug occurs within the first 3 months posttransplant in recipients' coadministered CsA. In the APOMYGRE
Targets for MPA exposure
In 2006, the conclusions of a roundtable meeting on TDM of MMF were published, and a therapeutic window for MPA AUC was proposed to be between 30 and 60 mg·h/L [4]. The upper limit of the therapeutic range was defined based on the lack of added efficacy (in the RCCT: Randomised Concentration Control Trial, there is no further reduction in acute rejection at AUC values exceeding 60 mg·h/L) and not based on the increased risk of toxicity. Based on several PK studies, the group recommended lower
Achieving therapeutic concentrations
Early adequate exposure to MPA is crucial for preventing acute rejection. However, multiple studies have shown that a fixed dose of 1 g twice daily results in underexposure in the critical early posttransplant period, particularly in CsA-treated patients. The recent APOMYGRE study [10] showed that in a fixed dose of MMF, the MPA AUC was less than 30 mg·h/L in 73%, 69%, and 44% of CsA-treated recipients on days 7, 14, and 30 after transplantation, respectively. The FDCC trial [11] also showed
Indications for TDM of mycophenolates
Indications for TDM of mycophenolates were reviewed in a previous consensus meeting [4]. They included high-risk patients, patients with delayed graft function, or patients with immunosuppressive protocols excluding induction therapy or steroids or CNI or patients with CNI minimization. Most of these patients (especially high-risk patients) are often excluded from the clinical trials. In fact, MPA TDM is currently only used in a few transplant centers on a routine basis, whereas a few others
Conclusions
The most compelling arguments in favor of TDM for MPA are the clear concentration-effect relationship and large interpatient variation. The importance of early exposure has been demonstrated in multiple trials, and many patients are under exposed at this critical period. Without TDM, it is not possible at the present time to predict who will be under- or overexposed. Individualization of MMF dose by TDM based on MPA AUC is a way for overcoming the problems of interpatient variability and time
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Model-informed precision dosing to optimise immunosuppressive therapy in renal transplantation
2021, Drug Discovery TodayCitation Excerpt :MPA displays substantial PK variability, a narrow therapeutic index, and an increasingly clear exposure–effect relationship.4 This has driven the personalisation of MPA therapy, with the consensus shifting toward AUC-guided TDM.4,32,33 The MPA C0 is uninformative for its AUC (R2 = 0.16–0.45),34 rendering it an unreliable marker for exposure assessment.
Therapeutic drug monitoring of immunosuppressive drugs in hepatology and gastroenterology
2021, Best Practice and Research: Clinical GastroenterologyLack of concordance between EMIT assay and LC-MS/MS for Therapeutic Drug Monitoring of Mycophenolic Acid: Potential increased risk for graft rejection?
2020, Journal of Pharmaceutical and Biomedical AnalysisCitation Excerpt :All statistical analysis were performed with Analyse-it v2.20; the data comparison was performed by Weighted Deming regression and the bias was calculated with Altman-Bland Test. The theoretical clinical significance of the bias was evaluated by determining the number and percentage of discordant indication from the TDM results obtained by EMIT and LC–MS/MS, considering 3 different lower cutoff values of MPA concentrations: 1.3 mg/L [17], 1.6 mg/L and 1.9 mg/L [11]. Fisher exact test was used for confirming the association between TDM indication of LC–MS/MS and EMIT, while McNemar (with binomial distribution) test was used for testing their discordance.
Population pharmacokinetics of mycophenolic acid in adult kidney transplant patients under prednisone and tacrolimus regimen
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2019, Kidney Transplantation - Principles and Practice
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Deceased.