Immunosuppression with mycophenolic acid: one size does not fit all.

Over the past decade, immunosuppression for renal transplantation has shifted from predominantly azathioprine-based regimens to those containing mycophenolic acid (MMF, CellCept) (1). In most centers, MMF is combined with cyclosporine or tacrolimus (calcineurin inhibitors) plus corticosteroid therapy. These combinations have led to unprecedented patient and graft survivals over the near term (1 to 3 yr) and low rates of acute rejection. The recommended MMF dose is standard for all patients at 1 g twice daily. Long-term survivals of patients and grafts are also improving but are suboptimal. Donor factors such as age, prolonged cold ischemia, and delayed graft function are associated with shortened graft half-life. The occurrence of acute rejection episodes remains a strong predictor of shortened allograft half-life and chronic allograft nephropathy. In this issue of JASN, Knoll et al. (2) present a retrospective study showing the rather obvious fact that there is a decreased time to first acute rejection if the recommended dose of MMF is reduced because of side effects. Furthermore, there is a quantitative relationship between the time the patient spends at less than the recommended dose and the risk for acute rejection. Although the study is flawed in design by its retrospective nature and its failure to examine important variables such as cytomegalovirus (CMV) status and the length of time the patient was on dialysis, this study does illustrate the difficulty clinicians have in using drugs that have no biologic end points for dose adjustment. The situation with MMF dosing is analogous to prescribing warfarin anticoagulation with no knowledge of INR but instead having to wait for bleeding or thrombosis before making dose adjustments. The consequences of long-term corticosteroid use and the nephrotoxic/metabolic side effects of calcineurin inhibitors are related to total drug exposure. For calcineurin inhibitors, we use pharmacokinetic parameters to allow individualization of therapy. With MMF, the current practice is that one size fits all. The data of Knoll et al. suggest that this is inadequate. It is difficult to ascribe cause and effect to the reduced MMF dose and acute rejection for several reasons. Cyclosporine and tacrolimus each have different pharmacokinetic interactions with mycophenolate mofetil, and they were used sequentially in the study. There is no adjustment for length of renal failure, which could influence bone marrow tolerance of MMF, particularly with second transplants. CMV infections, which can be associated with dose-limiting leukopenia, thrombocytopenia, and acute rejection, were not examined in this analysis, nor were renal function, liver function, and decreased drug-protein binding, all factors that increase mycophenolic acid exposure (3). Mycophenolic acid is prescribed as a morpholinoethyl ester, mycophenolate mofetil (MMF, CellCept). The ester linkage is rapidly cleaved to the active compound, mycophenolic acid. MMF blocks de novo purine biosynthesis by inhibition of inosine monophosphate dehydrogenase (IMPDH), thus decreasing the proliferation of T and B lymphocytes (4,5). The pharmacokinetics of MMF are complex; some patients achieve a peak in 1 to 2 h and a second peak at 5 to 6 h due to enterohepatic circulation. In some patients, the second peak (Cmax) is as much as 50% of the total peak concentration. A maximum concentration of 10 g/ml is associated with side effects. There is little correlation with area under the concentration curve (AUC) and dose. The AUC in the first 12 h does correlate with propensity to reject if it is 30 g h/ml or toxicity if it is 60 g h/ml. The desired exposure is 35 to 60 g h/ml (6,7). Mycophenolic acid AUC is increased by renal dysfunction, which may be clinically relevant early after transplantation or during rejection episodes (8,9). When heart transplant patients who had rejection were compared with patients who did not reject, doses were the same but rejecters had low AUC and trough levels (10). Most strategies to reduce steroids or to eliminate long-term nephrotoxic effects of calcineurin inhibitors presume adequate patient exposure to mycophenolic acid. This was true in the prematurely stopped NIH steroid withdrawal trial, where an excess of rejection episodes was seen in the patients who had steroids withdrawn. In African-American subjects in that trial, the dose of mycophenolic acid was only 200 mg more than in white patients; however, the rejection rate with steroid withdrawal was 40% in African Americans and 16% in non-African Americans. If indeed African Americans have increased propensity to reject and thus require larger doses of mycophenolate, one interpretation consistent with the data could be that inadequate mycophenolate was given to African-American patients (11). This type of analysis begs the question as to whether there are pharmacogenetic or gender differences in mycophenolate metabolism. Limited studies comparing pharmacokinetics parameters between African-American and white renal transplant patients have shown few differences, suggesting that the differences in rejection rates between Correspondence to: Dr. William M. Bennett, Solid Organ and Cellular Transplantation, Legacy Good Samaritan Hospital, 1040 NW 22 Avenue, Suite 480, Portland, OR 97210-3025. Phone: 503-413-7349; Fax: 503-413-6563; E-mail [email protected]