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Why and How to Perform Therapeutic Drug Monitoring for Mycophenolate Mofetil

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Why and How to Perform Therapeutic Drug Monitoring for Mycophenolate Mofetil Trends in Transplantation 2007;12007;1:24-34 Why and How to Perform Therapeutic Drug Monitoring for Mycophenolate Mofetil Brenda de Winter and Teun van Gelder Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus Medical Centre, Rotterdam, the Netherlands Abstract The introduction of the immunosuppressive agent mycophenolate mofetil as a standard-dose drug has resulted in a reduced risk of rejection after renal transplantation and improved graft survival compared to azathioprine. The favorable balance between efficacy and safety has made mycophenolate mofetil a cornerstone immunosuppressive drug, and the vast majority of newly transplanted patients are now started on mycophenolate mofetil therapy. Despite the obvious success of mycophenolate mofetil as a standard-dose drug, there is reason to believe that the “one size fits all” approach is not optimal. Recent studies have shown that the pharmacokinetics of mycophenolic acid are influenced by patient charac- teristics such as gender, time after transplantation, serum albumin concentration, renal function, co-medication, and pharmacogenetic factors. As a result, with standard-dose therapy there is wide between-patient variability in exposure of mycophenolic acid. This variability is of clinical relevance because it has repeatedly been shown that exposure to the active metabolite mycophenolic acid is correlated with the risk of developing acute rejection. Especially with the increasing popularity of immunosuppressive regimens in which the concomitant immunosuppression is reduced or eliminated, ensuring an appropri- ate level of immunosuppression afforded by mycophenolic acid is of utmost importance. By introducing therapeutic drug monitoring, mycophenolic acid exposure can be targeted to the widely accepted therapeutic window (mycophenolic acid AUC0-12 between 30 and 60 mg·h/l). Three prospective randomized studies comparing concentration-controlled my- cophenolate mofetil therapy to a fixed-dose regimen will further clarify the role of thera- peutic drug monitoring in increasing the therapeutic potential of mycophenolate mofetil. (Trends in Transplant 2007;1:24-34) Corresponding author: Teun van Gelder, [email protected] Key words Mycophenolate mofetil. Mycophenolic acid. Renal transplantation. Therapeutic drug moni- toring. Correspondence to: Teun van Gelder Department of Hospital Pharmacy Clinical Pharmacology Unit Erasmus Medical Centre Dr. Molewaterplein, 50 3015 Rotterdam, the Netherlands E-mail: [email protected] 24 Brenda de Winter and Teun van Gelder: Therapeutic Drug Monitoring for Mycophenolate Mofetil Why is there a need for therapeutic Introduction drug monitoring? Mycophenolate mofetil (MMF, Cellcept®, For a drug to be considered a suitable Roche) was introduced in 1995 for the prevention candidate for TDM a number of criteria need to of acute rejection in renal-allograft recipients1. be met. These criteria include a clear relationship The active metabolite mycophenolic acid (MPA) between drug concentration and effect, a small is a selective, reversible, noncompetitive inhibitor therapeutic index, and considerable between-pa- of inosine monophosphate dehydrogenase (IM- tient pharmacokinetic variability5. Several papers PDH). This enzyme is an important step in the de with recommendations on when and how to per- novo synthesis of guanine nucleotides. MPA in- form TDM for MMF have been published6,7. How- hibits T- and B-lymphocyte proliferation by inhibi- ever, in view of the cost and effort involved in tion of IMPDH activity, which ultimately results in performing TDM, more evidence for the validity its immunosuppressive effect. of a dose-individualization approach is needed A pooled efficacy analysis of the registra- as a basis for decision making in healthcare pol- tion trials found a significant decrease in the rate icy. Randomized, multicenter, prospective trials of rejection in renal-transplant recipients, from have been started to supply the highest grade of 40.8% in placebo or azathioprine treatment to evidence as well as a quantification of the impact 19.8 and 16.5% for the groups treated with MMF of TDM. In these trials, the added value of TDM of 2 g and 3 g, respectively2. The favorable balance MPA is investigated by comparing fixed-dose MMF between efficacy and safety has made MMF a cor- treatment with concentration-controlled treatment nerstone immunosuppressive drug, and the vast in de novo kidney transplant recipients. If such majority of newly transplanted patients are now studies show an improvement in clinical outcome started on MMF therapy3. Its lack of nephrotoxicity for patients in whom TDM is performed, compared has made MMF also very popular in reduced-tox- to a control group on standard-dose therapy, icity regimens, involving the minimization or with- then this will give further support to the implemen- drawal of calcineurin inhibitors or corticosteroids4. tation of routine pharmacokinetic monitoring and dose individualization. Remarkably, for cyclospo- Although MMF was initially introduced as a rine and tacrolimus, drugs for which routine TDM standard-dose drug at a fixed-dose regime of 1 g is performed worldwide, there have been no ran- orally twice daily, at present therapeutic drug mon- domized studies to examine the potential benefit itoring (TDM) is a frequently discussed topic that of TDM. Nevertheless, there is little controversy may further improve MMF therapy. In this review among clinicians that measuring cyclosporine and the determinants of variability in MPA exposure are tacrolimus in blood is a useful adjunct to their shown, and the rationale for TDM is discussed. optimal administration. In fact, the Fixed Dose ver- sus Concentration Controlled (FDCC) study, initi- We would like to emphasize that with the ated in 2003 and investigating the value of mon- increasing use of MMF in other types of solid- itoring MPA concentrations, is the first randomized organ transplantation, stem-cell transplantation, study for immunosuppressive drug monitoring8. and autoimmune diseases, the same issues al- ready do or will play a role. The need for TDM The rationale behind studies investigating may also apply to these indications. Furthermore, the potential of TDM for MMF is twofold. First, with we want to stress that because of different phar- standard-dose therapy there is wide between- macokinetics, the data in this manuscript only patient variability in exposure of MPA. And sec- relate to the MMF formulation and not to the en- ond, this variability is of clinical relevance as ex- teric-coated mycophenolic sodium or other (ge- posure to the active metabolite MPA is correlated neric) MPA formulations. with the risk of allograft rejection. 25 Trends in Transplantation 2007;1 MPA exposure and efficacy would think that because of the induction therapy, early drug exposure to MPA would not be so Several clinical studies with MMF have critical. In this study, however, the day three ex- shown that while no correlation was observed posure to MPA was an important predictor of acute between MMF dose and allograft rejection, the rejection. pharmacokinetic parameters of MPA did show a relationship with efficacy9-11. In these studies, it was shown that patients developing biopsy prov- Influence of co-therapy en acute rejection had lower drug exposure (ei- with cyclosporine or tacrolimus ther MPA AUC0-12 and/or predose levels) com- 12 pared to non-rejecting patients . The MPA AUC0-12 In the three registration studies and in the has a better correlation with the risk of rejection abovementioned studies, all included patients than predose levels10,13,14. were on CsA therapy co-therapy9-11. Currently, an increasing proportion of patients are being co- A hallmark study for the interest in measur- treated with tacrolimus3. The MPA pharmacoki- ing MPA levels was the Randomized Concentra- netics are different if MMF is used in combination tion-Controlled Trial (RCCT). In this study, 150 with tacrolimus or CsA. Increased MPA clearance renal-transplant patients treated with MMF, cyclo- and decreased-dose normalized concentrations sporin A (CsA) and prednisone for six months of MPA are found in CsA co-treated patients com- were randomized to three AUC target groups: low pared to tacrolimus co-therapy15. Although ini- (16.1 mg·h/l), intermediate (30.3 mg·h/l) and high tially it was unclear if it was CsA that caused a (60.6 mg·h/l). The patients in the low target MPA decrease in MPA exposure, or tacrolimus that AUC group had the highest risk of biopsy proven increased levels, the evidence now points to- acute rejection. Using logistic regression analy- wards a role for CsA. It was also shown that sis, a statistically significant relationship was found discontinuation of CsA in the immunosuppressive between the incidence of biopsy proven acute therapy leads to increased MPA predose levels16, rejection and MPA AUC (p < 0.001) and MPA C0 suggesting that the differences depend on an (p = 0.01), with the AUC showing the best cor- effect of CsA on the pharmacokinetics of MPA. relation10. Similar correlations between pharma- The “Creeping Creatinine-study”, where CsA was cokinetic parameters and outcome have been discontinued, showed an increased incidence of reported by the German study group on MMF anemia, despite improved allograft function, most therapy in pediatric renal-transplant patients9. likely due to a rise in MPA concentrations17,18. They found an increased risk for acute rejection in the first month posttransplantation in children
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