How Delayed Graft Function Impacts Exposure to Mycophenolic Acid in Patients After Renal Transplantation
ABSTRACT Mycophenolic acid (MPA) plasma concentrations are highly variable on standard-dose mycophenolate mofetil therapy. At creatinine clearances below 25 mL/min, MPA clearance increases as a result of a higher nonprotein-bound fraction. Patients with delayed graft function (DGF) after renal transplantation are exposed to low total MPA concentrations, when risk of rejection is highest. This study investigated the influence of DGF on MPA exposure and on clinical outcome.
Adult renal transplantation patients treated with mycophenolate mofetil, corticosteroids, and either microemulsified cyclosporine (n = 459) or tacrolimus (n = 371) participated in a randomized controlled trial (the Fixed-Dose Concentration-Controlled [FDCC] Study). Abbreviated MPA areas under the curve (AUCs) were obtained on Day 3, Day 10, Week 4, and Month 3, to calculate MPA AUC₀₋₁₂. Free MPA AUC values were available for a subgroup of patients (n = 269).
The overall incidence of DGF was 187 of 830 (23%) and did not differ between cyclosporine-treated (24%) and tacrolimus- (21%) treated patients. The incidence of biopsy-proven acute rejection at 12 months was significantly higher in patients with DGF (13.8% versus 21.4%). Patients with DGF had significantly lower dose-corrected MPA AUC on Day 3 and Day 10. Free MPA fraction and dose-corrected free MPA AUC were significantly higher in patients with DGF, from Day 3 until Month 3. The total number of patients with at least one opportunistic infection was significantly higher in patients with DGF (33.2%) compared with patients without DGF (25.8%) (P = 0.048). Patients with DGF developing opportunistic infections did not have higher total MPA AUC nor higher free MPA AUC compared with those without opportunistic infections.
Patients with DGF have significantly lower dose-corrected MPA AUC in the first month after renal transplantation, presumably as a result of enhanced MPA clearance on account of the elevated MPA free fraction. Because patients with DGF have a higher rate of acute rejection and lower MPA exposure, higher dosing of mycophenolate mofetil in such patients may improve outcome. However, the already increased incidence of opportunistic infections in patients with DGF is a concern.
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ABSTRACT: This review aims to provide an update of the literature on the pharmacology and toxicology of mycophenolate in solid organ transplant recipients. Mycophenolate is now the antimetabolite of choice in immunosuppressant regimens in transplant recipients. The active drug moiety mycophenolic acid (MPA) is available as an ester pro-drug and an enteric-coated sodium salt. MPA is a competitive, selective and reversible inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), an important rate-limiting enzyme in purine synthesis. MPA suppresses T and B lymphocyte proliferation; it also decreases expression of glycoproteins and adhesion molecules responsible for recruiting monocytes and lymphocytes to sites of inflammation and graft rejection; and may destroy activated lymphocytes by induction of a necrotic signal. Improved long-term allograft survival has been demonstrated for MPA and may be due to inhibition of monocyte chemoattractant protein 1 or fibroblast proliferation. Recent research also suggested a differential effect of mycophenolate on the regulatory T cell/helper T cell balance which could potentially encourage immune tolerance. Lower exposure to calcineurin inhibitors (renal sparing) appears to be possible with concomitant use of MPA in renal transplant recipients without undue risk of rejection. MPA displays large between- and within-subject pharmacokinetic variability. At least three studies have now reported that MPA exhibits nonlinear pharmacokinetics, with bioavailability decreasing significantly with increasing doses, perhaps due to saturable absorption processes or saturable enterohepatic recirculation. The role of therapeutic drug monitoring (TDM) is still controversial and the ability of routine MPA TDM to improve long-term graft survival and patient outcomes is largely unknown. MPA monitoring may be more important in high-immunological recipients, those on calcineurin-inhibitor-sparing regimens and in whom unexpected rejection or infections have occurred. The majority of pharmacodynamic data on MPA has been obtained in patients receiving MMF therapy in the first year after kidney transplantation. Low MPA area under the concentration time from 0 to 12 h post-dose (AUC0-12) is associated with increased incidence of biopsy-proven acute rejection although AUC0-12 optimal cut-off values vary across study populations. IMPDH monitoring to identify individuals at increased risk of rejection shows some promise but is still in the experimental stage. A relationship between MPA exposure and adverse events was identified in some but not all studies. Genetic variants within genes involved in MPA metabolism (UGT1A9, UGT1A8, UGT2B7), cellular transportation (SLCOB1, SLCO1B3, ABCC2) and targets (IMPDH) have been reported to effect MPA pharmacokinetics and/or response in some studies; however, larger studies across different ethnic groups that take into account genetic linkage and drug interactions that can alter a patient's phenotype are needed before any clinical recommendations based on patient genotype can be formulated. There is little data on the pharmacology and toxicology of MPA in older and paediatric transplant recipients.Archives of Toxicology 05/2014; DOI:10.1007/s00204-014-1247-1 · 5.08 Impact Factor
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ABSTRACT: Efficient rejection prophylaxis and excellent short-term results in organ transplantation can not obscure the fact that long-term outcomes have not improved substantially over the last decade with rather constant graft attrition rates beyond the first year. There remains an unmet medical need for new immunosuppressive regimens to improve long-term graft and patient survival while carrying a low side effect burden. Several trials in renal transplant recipients are in the planning stages. In general there are two major strategies to improve outcomes: (a) the constant evolution of new immunosuppressive regimens with the currently approved immunosuppressants, and/or (b) the use of novel immunosuppressants. In this review, we give an overview of the most recent developments of novel immunosuppressive regimes. We show promising new immunosuppressive drugs and new immunosuppressive strategies serving as potential alternative's for calcineurin inhibitor-based regimens. Such regimens should provide similar efficacy and eventually better tolerability or a different side-effect profile with clinical benefits.Transplantation Proceedings 04/2013; 45(3):1224-31. DOI:10.1016/j.transproceed.2013.02.033 · 0.95 Impact Factor
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ABSTRACT: BACKGROUND: Although mycophenolate mofetil (MMF) is recommended at a fixed dose, there is increasing interest in controlled-dose (CD) MMF based on therapeutic drug monitoring. We systematically evaluated published randomized controlled trials (RCTs) on the efficacy and safety of CD versus fixed-dose MMF for kidney transplant recipients. METHODS: The electronic databases Medline, Embase, and Cochrane Library (up to June 2012) were searched to identify relevant RCTs. Two reviewers independently applied the study selection criteria, examined the study quality, and extracted the data. Dichotomous measures were expressed as relative risk (RR) and continuous outcomes were expressed as weighted mean difference, both with 95% confidence intervals (CIs). All statistical analyses were performed using Review Manager 5.1.6. RESULTS: Four RCTs met our selection criteria and included 1755 de novo recipients. The differences between CD and fixed-dose MMF in treatment failure (RR, 0.95; 95% CI, 0.82-1.10; P=0.52), serum creatinine clearance (weighted mean difference, 2.46; 95% CI, -1.15 to 6.07; P=0.18), total gastrointestinal adverse events (RR, 1.23; 95% CI, 0.65-2.35; P=0.53), diarrhea (RR, 1.08; 95% CI, 0.92-1.25; P=0.35), anemia (RR, 1.24; 95% CI, 0.95-1.64; P=0.12), leukopenia (RR, 1.12; 95% CI, 0.93-1.35; P=0.25), thrombocytopenia (RR, 0.80; 95% CI, 0.47-1.36; P=0.41), and malignancy (RR, 0.61; 95% CI, 0.27-1.38; P=0.23) were not statistically significant. Furthermore, total infections were more frequent in the CD group (36.0% vs. 30.9%; RR, 1.16; 95% CI, 1.03-1.30; P=0.01). CONCLUSIONS: Based on current evidence, CD MMF administration cannot be recommended as routine practice for kidney transplant recipients. Therapeutic drug monitoring for MMF may be targeted toward high-risk recipients, who should be identified in future studies.Transplantation 04/2013; 96(4). DOI:10.1097/TP.0b013e31828c6dc7 · 3.78 Impact Factor