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Home , Mycophenolic acid, Sirolimus

J Am Soc Nephrol 14: 2414–2416, 2003 with : One Size Does Not Fit All

WILLIAM M. BENNETT Northwest Renal Clinic, Legacy Good Samaritan Hospital, Portland, Oregon.

Over the past decade, immunosuppression for renal transplan- different pharmacokinetic interactions with mycophenolate tation has shifted from predominantly -based reg- mofetil, and they were used sequentially in the study. There is imens to those containing mycophenolic acid (MMF, CellCept) no adjustment for length of renal failure, which could influence (1). In most centers, MMF is combined with cyclosporine or bone marrow tolerance of MMF, particularly with second ( inhibitors) plus corticosteroid therapy. transplants. CMV infections, which can be associated with These combinations have led to unprecedented patient and dose-limiting , , and acute rejec- graft survivals over the near term (1 to 3 yr) and low rates of tion, were not examined in this analysis, nor were renal func- acute rejection. The recommended MMF dose is standard for tion, function, and decreased drug-protein binding, all all patients at 1 g twice daily. factors that increase mycophenolic acid exposure (3). Long-term survivals of patients and grafts are also improv- Mycophenolic acid is prescribed as a morpholinoethyl ester, ing but are suboptimal. Donor factors such as age, prolonged mycophenolate mofetil (MMF, CellCept). The ester linkage is cold ischemia, and delayed graft function are associated with rapidly cleaved to the active compound, mycophenolic acid. shortened graft half-life. The occurrence of acute rejection MMF blocks de novo by inhibition of episodes remains a strong predictor of shortened allograft monophosphate dehydrogenase (IMPDH), thus decreasing the half-life and chronic allograft nephropathy. In this issue of proliferation of T and B (4,5). The JASN, Knoll et al. (2) present a retrospective study showing the of MMF are complex; some patients achieve a peak in 1 to2hand rather obvious fact that there is a decreased time to first acute a second peak at 5 to 6 h due to enterohepatic circulation. In some rejection if the recommended dose of MMF is reduced because patients, the second peak (Cmax) is as much as 50% of the total of side effects. Furthermore, there is a quantitative relationship peak concentration. A maximum concentration of Ͼ10 ␮g/ml is between the time the patient spends at less than the recom- associated with side effects. There is little correlation with area mended dose and the risk for acute rejection. under the concentration curve (AUC) and dose. The AUC in the Although the study is flawed in design by its retrospective first 12 h does correlate with propensity to reject if it is Ͻ 30 nature and its failure to examine important variables such as ␮g ⅐ h/ml or toxicity if it is Ͼ60 ␮g ⅐ h/ml. The desired exposure (CMV) status and the length of time the is 35 to 60 ␮g ⅐ h/ml (6,7). Mycophenolic acid AUC is increased patient was on dialysis, this study does illustrate the difficulty by renal dysfunction, which may be clinically relevant early after clinicians have in using drugs that have no biologic end points transplantation or during rejection episodes (8,9). When heart for dose adjustment. The situation with MMF dosing is anal- transplant patients who had rejection were compared with patients ogous to prescribing warfarin anticoagulation with no knowl- who did not reject, doses were the same but rejecters had low edge of INR but instead having to wait for or throm- AUC and trough levels (10). bosis before making dose adjustments. The consequences of Most strategies to reduce steroids or to eliminate long-term long-term corticosteroid use and the nephrotoxic/metabolic nephrotoxic effects of calcineurin inhibitors presume adequate side effects of calcineurin inhibitors are related to total drug patient exposure to mycophenolic acid. This was true in the exposure. For calcineurin inhibitors, we use pharmacokinetic prematurely stopped NIH steroid withdrawal trial, where an ex- parameters to allow individualization of therapy. With MMF, cess of rejection episodes was seen in the patients who had the current practice is that one size fits all. The data of Knoll steroids withdrawn. In African-American subjects in that trial, the et al. suggest that this is inadequate. It is difficult to ascribe dose of mycophenolic acid was only 200 mg more than in white cause and effect to the reduced MMF dose and acute rejection patients; however, the rejection rate with steroid withdrawal was for several reasons. Cyclosporine and tacrolimus each have 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 Correspondence to: Dr. William M. Bennett, Solid Organ and Cellular Trans- consistent with the data could be that inadequate mycophenolate plantation, Legacy Good Samaritan Hospital, 1040 NW 22nd Avenue, Suite 480, Portland, OR 97210-3025. Phone: 503-413-7349; Fax: 503-413-6563; was given to African-American patients (11). This type of anal- E-mail [email protected] ysis begs the question as to whether there are pharmacogenetic or 1046-6673/1409-2414 gender differences in mycophenolate metabolism. Limited studies Journal of the American Society of comparing pharmacokinetics parameters between African-Amer- Copyright © 2003 by the American Society of Nephrology ican and white renal transplant patients have shown few differ- DOI: 10.1097/01.ASN.0000087540.41388.AD ences, suggesting that the differences in rejection rates between J Am Soc Nephrol 14: 2414–2416, 2003 Immunosuppression with Mycophenolic Acid 2415 these two populations are not explained by pharmacokinetic dif- dynamic studies to look at reductions in IMPDH, but no clinically ferences alone but are more likely related to differences in innate relevant information is currently available (20,21). immunologic response (12). There are a host of studies examining steroid avoidance, It is a common sense notion that a fixed dose is inadequate steroid withdrawal, calcineurin inhibitor withdrawal, and dose for patients with large interindividual variations in pharmaco- minimization. The available data are summarized nicely by kinetics and pharmacodynamics. To use the same 2-g daily Bodziak et al. (22) and Vincenti et al. (23) The primary end dose of mycophenolate given to a 100-kg man and a 50-kg point for these trials is usually percent acute rejection episodes women does not seem logical. after drug withdrawal. Even though these episodes are gener- The frequency of adverse reactions both gastrointestinal (GI) ally reversible, the long effects of these minimization strategies and hematologic seen by Knoll et al. fit other series in the on graft half lives are unknown. The role of (Rapam- literature. It is common clinical experience that few patients, even mune) in minimization regimens is also under investigation. African-American patients, can tolerate 3 g/d MMF. The GI side While patients usually improve renal function when cal- effects of MMF can be serious. Erosive enterocolitis can be seen. cineurin inhibitors are withdrawn and sirolimus is substituted, In some patients, infectious etiologies can be found, but dose the long-term effects of these strategies are also unknown. It reduction is usually required for symptomatic relief (13,14). should be remembered that there may be pharmacokinetic Another interesting aspect of mycophenolic acid pharmacol- and/or pharmacodynamic interactions that could reduce renal ogy is the increase in AUC with time from transplant despite a function when sirolimus and calcineurin inhibitors are used constant dose (15). Adequate exposure to the drug in the first together. In fact, the pivotal studies used for sirolimus approval 3 mo is important to prevent rejection, whereas GI and hema- showed worse renal function at 1 yr, despite reduction of acute tologic side effects may occur later with the same dose. In rejection episodes (24–26). Since long-term results continue to practice, most clinicians start at 1 g twice daily and titrate the improve, the burden of proof for any new regimen is high. patient to or cytopenias, ending with the maximum Studies defining appropriate pharmacokinetic targets and dose that avoids these complications. correlation with efficacy and toxicity are urgently needed to Are there better ways to give this valuable drug? There has maximize the therapeutic potential of mycophenolic acid. been some anecdotal success in preparing emulsions of myco- We are living in an era with increasing choices for immuno- phenolate instead of capsules. Also splitting the dose 3 to 4 suppressive regimens. The federal government is the main payor times in a 24-h period instead of twice with minimization of for immunosuppressive medications for the first 44 mo after

Cmax can avoid GI symptoms (14). transplantation under Medicare (hopefully extended by political An enteric-coated formulation of mycophenolate sodium persuasion from our professional societies); therefore, nephrolo- (Myfortic) is in the final stages of drug development. Presum- gists have a responsibility to be good stewards of the govern- ably the enteric coating avoids upper GI tract toxicity and ment’s money. Therapeutic decisions should be based on well- delivers the drug more distally, where it may be absorbed designed clinical trials. Most trials of new drugs are by necessity better. Randomized blinded trials are in progress, but thus far funded by drug manufacturers. In addition, generic versions of there is no evidence that this formulation has a better efficacy Sandimmune and Neoral are now available with other patented or side effect profile than MMF. drugs to follow. Minor formulation changes for tacrolimus (Pro- Most of the rejection reactions that were seen in the study of graf) are in the works. In a free marketplace, competition should Knoll et al. were mild and reversible without any change in reduce prices for the government and consumers. The experience 1-yr graft survival (2). Whether these rejections compromise to date has been disappointing in that the cost savings are not long-term graft function is unknown. In a recent analysis of the passed on to either the payor or consumers. UNOS database, rejection rates in a cohort from 1998–2000 With the results of renal transplant being excellent now, we ranged between 21 and 32%, thus the rejection rate of 24% in hope that real therapeutic advances will be corroborated by con- this study appears consistent with those numbers (16). trolled, blinded studies. The data reported by Shah et al. (27) The major metabolite of mycophenolic acid is mycophenolic comparing blinded and open studies with Neoral versus Sandim- acid glucuronide (MPG). MPA is metabolized by an enzymatic mune are instructive. Blinded studies showed little difference in process mediated by UDP-glucuronosyl transferase (UDPGT) efficacy and toxicity, while open studies favored the newer agent (17). Although cyclosporine exhibits a dose-dependent inhibi- made by the same manufacturer. We foresee this scenario re- tion of this reaction, thus increasing mycophenolic acid con- played with Prograf compared with an extended release prepara- centrations, tacrolimus is 60-fold more efficient as an inhibitor tion of the same drug, the closely related drugs sirolimus and of this reaction (18,19). In patients with delayed graft function, , and certainly for mycophenolic acid in the CellCept AUC of MPG, the free fraction of MPA and the AUC of formulation versus an enteric-coated formulation (Myfortic). Ge- free-MPA are all increased. These perturbed pharmacokinetics neric alternatives to all these immunosuppressive drugs will be improve with resumption of normal renal function (8). available as patents expire. It is imperative that physicians, pa- We might improve the therapeutic index of MMF by pharma- tients, and dispensing pharmacists be acquainted with the guide- cokinetic modeling. There are as yet no agreed-upon guidelines or lines set out by the recent American Society of Transplantation target levels for such monitoring. Furthermore, the optimal timing Consensus Conference on generics, which urge caution in switch- of drug monitoring, whether Cmax, trough, or AUC, correlate ing from one preparation to another without adequate bioequiva- better with clinical events is unclear. There have been pharmaco- lence data being obtained in transplant recipients (28). 2416 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 2414–2416, 2003

In 2003, we are doing well in renal transplantation outcomes 13. Maes BD, Dalle I, Geboes K, Oellerich M, Armstrong VW, even with our nonspecific immunosuppressive therapy. Improve- Evenepoel P, Geypens B, Kuypers K, Shipkova M, Geboes K, ments in efficacy and long-term safety will come from tolerance Vanrenterghem YFC: Erosive enterocolitis in mycophenolate protocols that minimize the need for generalized immunosuppres- mofetil-treated renal-transplant recipients with persistent afebrile sion and by obtaining sound scientific evidence for any changes in diarrhea. Transplantation 75: 665–672, 2003 14. Behrend M: Adverse gastrointestinal effects of mycophenolate mofetil: our basic protocols. While using one dose for all patients is Aetiology, incidence and management. Drug Safety 24: 645–663, 2001 simple, it runs the risk of toxicity and underimmunosuppression. 15. 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See related article, “Mycophenolate Mofetil Dose Reduction and the Risk of Acute Rejection Following Renal Transplantation,” on pages 2381–2386.