Mycophenolic acid trough level monitoring in solid organ transplant recipients treated with mycophenolate mofetil: association with clinical outcome
ABSTRACT Mycophenolate mofetil (MMF) is widely and successfully used in immunosuppressive regimens for the prophylaxis of organ rejection following transplantation. Conventionally, it is administered at a fixed dose without serial measurements of plasma concentrations of mycophenolic acid (MPA), the active metabolite. Recently, there has been an increased interest in therapeutic drug monitoring (TDM) of MMF therapy to optimize the benefit/risk index of the drug. Predose trough samples of MPA are considered most convenient and economic, thereby allowing an increased use of TDM in the transplant setting. However, the added value of TDM for MMF therapy is still under debate.
This paper reviews (based on a systematic PubMed and EMBASE search, 1995-June 2006) the current evidence of the usefulness and clinical relevance of MPA trough level monitoring during MMF therapy in solid organ transplantation.
Based on data available in the public domain, the contribution of MPA trough level monitoring during MMF therapy in solid organ transplant recipients remains unproven. Available studies have limitations and report conflicting results. There is a lack of prospective randomized trials, particularly in pediatric renal transplant recipients and in cardiac and liver transplantation. While there is a suggestion that there may be a relationship between efficacy and MPA trough levels, the majority of studies showed no correlation between MPA plasma concentrations and adverse effects. Based on current evidence, the adherence to presently recommended target ranges for MPA troughs in solid organ transplantation cannot assure an improved clinical outcome with MMF therapy. Whether MPA trough level monitoring leads to improved efficacy and less toxicity is currently subject to a large randomized trial; final results are eagerly awaited.
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ABSTRACT: Information is lacking concerning concomitant administration of enteric-coated mycophenolate sodium with tacrolimus (EC-MPS+Tac) in renal transplant recipients (RTxR). In this 6-month, prospective, open-label, multicenter study, de novo RTxR were randomized (1 : 1) to low-dose (LD) or standard-dose (SD) Tac with basiliximab, EC-MPS 720 mg bid, and steroids. Primary objective was to compare renal function at 6-month posttransplantation. Secondary objectives were to compare the incidences of biopsy-proven acute rejection (BPAR), graft loss and death, and new-onset diabetes mellitus (NODM). 292 patients (LD n = 151, SD n = 141) were included. Mean Tac levels were at the low end of the target range in standard-exposure patients (SD, n = 141) and exceeded target range in low-exposure patients (LD = 151) throughout the study. There was no significant difference in mean glomerular filtration rate (GFR) between treatments (ITT-population: 63.6 versus 61.0 mL/min). Incidence of BPAR was similar (10.6% versus 9.9%). NODM was significantly less frequent in LD Tac (17% versus 31%; P = 0.02); other adverse effects (AEs) were comparable. EC-MPS+Tac (LD/SD) was efficacious and well tolerated with well-preserved renal function. No renal function benefits were demonstrated, possibly related to poor adherence to reduced Tac exposure.Journal of Transplantation 01/2012; 2012:941640. DOI:10.1155/2012/941640
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ABSTRACT: Recently, mycophenolic acid drugs have gained interest in the treatment of autoimmune diseases. However, only limited pharmacokinetic data are available on enteric-coated mycophenolate sodium in non-transplant indications. This study compared the pharmacokinetics of mycophenolic acid from enteric-coated mycophenolate sodium in patients with autoimmune disease and renal transplant recipients. Twelve autoimmune disease patients (mainly with antineutrophil cytoplasmic antibody-associated vasculitis) and 11 stable renal transplant patients, all of whom had been on enteric-coated mycophenolate sodium for > or = 10 weeks, received an oral dose of enteric-coated mycophenolate sodium of 720 mg under fasting conditions. Blood samples for the determination of mycophenolic acid in the plasma were collected over 24 h. Overall, no significant difference was found between both groups for their 0 - 12 h and 0 - 24 h areas under the concentration-time curve, C(max), T(max), C(0 h), C(12 h) and C(24 h), although the mean C(max) was numerically higher by 39% in the autoimmune disease patients (autoimmune disease 27.3 +/- 17.4 mg/l and renal transplant 19.6 +/- 15.7 mg/l). Patients on concomitant ciclosporin tended to have a lower mycophenolic acid exposure than patients on a non-ciclosporin regimen. The intersubject variabilities in the mycophenolic acid pharmacokinetics were high in both patient populations (around 40% for the area under the curve values). Both groups exhibited a weak and non-significant correlation between their mycophenolic acid trough (C(12 h)) levels and mycophenolic acid 0 - 12 h area under the curve (autoimmune disease r = 0.482 and renal transplant r = 0.138), whereas in the autoimmune disease group the mean C(1.5 h) and C(2 h) concentrations provided a satisfactory association with the 0 - 12 h area under the curve (for both r > 0.7 and p < 0.001). These data suggest that mycophenolic acid exposure (in terms of the area under the curve) from enteric-coated mycophenolate sodium is comparable in autoimmune disease and renal transplant patients. The mycophenolic acid trough levels did not reflect the systemic exposure to mycophenolic acid adequately; a limited sampling strategy for estimating mycophenolic acid exposure in autoimmune disease patients should include times around C(1.5 h) and/or C(2 h) reflecting T(max) if further studies confirm its usefulness.Expert Opinion on Pharmacotherapy 05/2008; 9(6):879-86. DOI:10.1517/146565184.108.40.2069 · 3.09 Impact Factor