Mycophenolate Blood Level Monitoring: Recent Progress

Transcription

1 American Journal of Transplantation 2009; 9: Wiley Periodicals Inc. Minireview C 2009 The Author Journal compilation C 2009 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /j x Mycophenolate Blood Level Monitoring: Recent Progress T. van Gelder Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands Corresponding author: Teun van Gelder, t.vangelder@erasmusmc.nl The concentration effect relationship for mycophenolic acid (MPA), and the high variability in MPA concentrations in patients on standard dose mycophenolate mofetil (MMF) therapy, for some centers has provided enough evidence to implement therapeutic drug monitoring (TDM) for MMF in daily practice. Two randomized trials Adaption de Posologie du MMF en Greffe Renale (APOMYGRE) and fixed-dose versus concentration controlled (FDCC) investigated the added benefit of TDM for MMF in renal transplant recipients. The APOMYGRE study showed a significant reduction in the incidence of acute rejection in concentrationcontrolled patients, while the FDCC study had a negative outcome, despite a similar study design. Although it was expected that these prospective trials would give the final answer to the question of whether or not TDM for MMF would be of benefit, it seems that the studies have not had much impact on patient management. Several trials have shown the importance of early adequate exposure to MPA in the first week after transplantation. As it will be hard to improve MPA exposure with TDM, this early, ongoing study now investigates the use of an increased starting dose. The increased starting dose will avoid underexposure to MPA in higher proportions of patients shortly after transplantation but may result in more toxicity in patients with MPA exposures exceeding the upper threshold of the therapeutic window. Key words: Monitoring, mycophenolate mofetil, mycophenolic acid, pharmacology, therapeutic drug monitoring Received 01 February 2009, revised 25 March 2009 and accepted for publication 26 March 2009 Therapeutic Drug Monitoring for Immunosuppressive Drugs Mycophenolic acid (MPA) was introduced as mycophenolate mofetil (MMF) and as a drug for which no TDM was considered necessary. Although there are some striking differences between countries, the vast majority of transplant centers throughout the world has maintained the one size fits all dosing strategy. TDM has been adopted only by some, and the added value of TDM for MPA is under debate (1). However, for MPA a concentration effect relationship has repetitively been shown, and several assays for measurement of MPA are available. In this minireview, the literature on TDM for MMF is reviewed and the two published randomized trials are compared. All data presented relate to the MMF formulation, as the enteric-coated mycophenolate sodium (EC-MPS) formulation has more variable pharmacokinetics (PKs) and TDM for EC-MPS has not been formally tested (2). High Immunosuppressive Load in First Weeks The risk of acute rejection is highest in the first weeks after transplantation. Target concentrations for the immunosuppressive drugs for which we perform TDM are highest in the first months, and dosages of corticosteroids are gradually tapered over time. For maintenance therapy, the lowest possible dose or target concentration is strived for. For MPA, with a fixed-dose strategy, the opposite is the result. Several PK studies have shown that in the first year after transplantation the clearance of MPA decreases, and that MPA exposure gradually increases over time (3). When MPA concentrations were not at all measured, we were unaware of this structural decrease in clearance over time after renal transplantation. Now that we do know that MPA concentrations are highest at a time when there is the least need for high concentrations, it would be good to reconsider if this is the desired approach. It is counterintuitive that MPA exposure increases over time, and is highest when it is least needed. Between-patient variability in pharmacokinetics For all of the drugs for which TDM is being performed, the dose is a poor predictor of exposure. Extensive betweenpatient variability has also been demonstrated for MPA. Population PK studies have identified several determinants that explain the interindividual differences in apparent oral clearance of MPA (4,5). The most important determinants for the variability are renal function, albumin levels and type of CNI cotherapy (6). Pharmacogenetic factors can explain only a relatively small part (7). In a fixed-dose regimen, the 1495

2 van Gelder MPA-area under the concentration versus time curve (AUC) in a patient on 2 g of MMF can be anywhere between 15 and 115 mg h/l. When MPA plasma concentrations are not checked, the physician is unaware if the patient is in the very low range of MPA exposure, in the very high range or somewhere in between. Some clinicians are reluctant to increase MMF doses based on measurement of subtherapeutic MPA concentrations, and would fear the occurrence of side effects in patients treated with 3 g MMF daily. Objectively seen, a 3 g MMF dose in a patient with a measured MPA-AUC of 55 mg h/l is safer than a 2 g MMF dose in a patient in whom, without knowing, the MPA-AUC is anywhere above 60 mg h/l. The latter is now the case in some patients on fixed-dose MMF therapy. Concentration effect relationship: efficacy In the randomized concentration-controlled trial (RCCT), adult patients were randomized for three groups with a different target MPA-AUC (8). A pharmacokinetic/ pharmacodynamic (PK/PD) analysis showed that MPA-AUC and, to a lesser extent, also MPA predose concentrations were significantly related to acute rejection. Another study showed similar data for pediatric renal transplant patients, again reporting higher risk of rejection in patients with low MPA-AUC (9). Largely based on these two studies, both of which were ciclosporin (CsA) based, a putative therapeutic window for MPA-AUC was defined. The lower threshold of this window was based on an increased risk of acute rejection for patients with a MPA-AUC below 30 mg h/l. The upper threshold of 60 mg h/l was based on little additional gain in efficacy if MPA-AUC exceeded this value. The more recent Caesar study, investigating a quadruple immunosuppressive regimen consisting of daclizumab, MMF, corticosteroids and CsA, has confirmed the concentration effect relationship for full-dose CsA cotherapy, with a therapeutic window for MPA-AUC between 30 and 60 mg h/l as optimal exposure. In the Caesar study, however, also two groups with reduced CsA target concentrations were included, aiming for target CSA trough levels of ng/ml (10). In those two groups, it was shown that acute rejection incidence has not yet reached a plateau at MPA- AUC values of mg h/l, but that higher MPA exposure up to a MPA-AUC of 75 mg h/l would offer additional efficacy. As the Caesar study was not specifically designed to study the concentration effect relationship, the authors do acknowledge that this result is purely descriptive and a confirmation of this observation in a second study is much needed. Concentration effect relationship: toxicity While the majority of studies confirmed the concentration efficacy relationship, the correlation between MPA exposure and toxicity is less convincing. The gastrointestinal side effects of MPA do not seem to be related to MPA plasma concentrations. Hematological toxicity in a number of studies was found to be related to the nonprotein bound MPA concentrations (11). As these free MPA levels remarkably do not appear to be related to efficacy, and as analytical methods to measure free MPA are more complex, it is not likely that monitoring free MPA will be pursued further. An exception may be the measurement of free MPA concentrations in patients with severely impaired renal function, in the immediate posttransplant period. As these patients typically have low total MPA concentrations, caused by a higher MPA clearance, physicians are facing a difficult dilemma. Based on the low total MPA exposure, dose increments would be required. If, however, the biological effect of the drug is better correlated with the nonprotein bound fraction, then the dose would be fine. At present, in patients with DGF, MMF should be dosed according to the package insert, i.e. not exceed the 2 g daily dose. Measurement of free MPA concentrations cannot be recommended, and it would be hard to give guidance regarding target values for free MPA. Also monitoring plasma concentrations of the acylglucuronide (Acyl-MPAG) does not seem to predict toxicity. Acyl-glucuronides can compromise protein function as a result of chemical modification and enterocolitis may be one of the clinical sequels of Acyl-MPAG toxicity (12). Heller et al., however, found no difference in Acyl-MPAG concentrations between patients with and without diarrhea (13). The weak relationship between MPA exposure and toxicity also explains why for the upper threshold of the therapeutic window a lack of additional efficacy was chosen rather than an increased occurrence of adverse events. Whether long-term toxicity of MPA is related to plasma concentrations is unclear. There are no PK/PD studies investigating the occurrence of malignancies, BK virus nephropathy or opportunistic infections as a function of MPA exposure. Whether the lack of evidence for increased long-term toxicity associated with overexposure to MPA means that there is no need for an upper threshold for the therapeutic window is a matter of debate. For those who believe that there is no concern regarding MPA exposures exceeding the upper boundary of the therapeutic window, a strategy of using a loading dose of MMF for a number of weeks can be an attractive alternative to therapeutic drug monitoring. With a higher dose, for example 4 g daily in the first2weeks,followedby3gdailyinthenext4weeks posttransplantation and then 2 g daily thereafter, virtually all patients have MPA-AUC values that are above the lower threshold of 30 mg h/l. Thereafter, patients would then go back to the more conventional MMF doses. Whether or not such high dosages and high MPA exposures put patients at risk for safety concerns remains to be seen, and overimmunosuppression may occur. Protagonists of TDM would agree that the increased dose in itself is a good strategy to ensure adequate MPA levels at an early stage after transplantation. The increased starting dose is likely to result in improvement of short-term efficacy. However, if combined with the measurement of MPA exposure after a number of days it would be possible to identify those patients in whom MPA-AUC reaches exceedingly high values, 1496 American Journal of Transplantation 2009; 9:

3 Mycophenolate Blood Level Monitoring allowing for dose reductions, reduced medication cost and possibly improved safety. Liver transplantation Compared to the number of studies performed in kidney transplant patients, the experience with TDM for MPA in liver transplantation is much smaller. The between-patient variability in the PKs of MPA in liver transplant patients is similar to renal transplantation (14). Tredger et al. related predose MPA concentrations to adverse events and rejection in 147 adults and 63 MMF treated pediatric liver recipients (15). They concluded that MPA predose level monitoring is both clinically and cost-effective and suggested a therapeutic range of mg/l. Prospective randomized trials comparing a strategy of TDM with standard dosing in liver transplant patients have not been done, and TDM for MPA in liver transplantation has not gained widespread popularity. Heart transplantation Also in heart transplantation, there are few studies that have investigated the value of monitoring MPA concentrations. The first to do so was the study by Meiser et al., published in 1999, performed in heart transplant patients treated with tacrolimus and MMF (16). In a first phase, while patients were on a fixed MMF dose of 2 g daily, an incidence of acute rejection of 66.7% (in 15 patients) was found. In this small group of patients, mean MPA predose levels above 3.0 mg/l were not associated with rejection. In phase II (30 patients), doses were adjusted according to MPA plasma levels (target range mg/l), and diagnoses of rejection were made in only 10.0% of patients. In a larger set of heart transplant patients, Yamani et al. confirmed an increased risk of acute rejection in patients with MPA predose levels below 2.0 mg/l (17). DeNofrio found better correlations when using MPA-AUC, with MPA-AUC values lower in patients with grade 2/3 acute rejections than in patients with grade 0 (26.1 vs mg h/l) rejections (18). Nontransplanted patients MMF is now increasingly being tested in a number of other areas, including autoimmune disease. Preliminary studies show that also here a MPA concentration effect relationship exists (19). This is not unexpected as, other than in transplantation, patients with autoimmune disease are often treated with only one immunosuppressive drug at a time (20). Inadequate plasma concentrations of this single drug cannot be compensated for by concomitantly given immunosuppressives. Randomized prospective trials It was expected that prospective randomized trials would give the final answer to the question of whether or not TDM for MMF would be of added benefit in the treatment of transplant patients. Two such trials in renal transplant patients have now been published. The first, Adaption de Posologie du MMF en Greffe Renale (APOMYGRE) study was a randomized trial, performed in 11 centers in France (21). Adult patients, receiving a first or second transplant, were randomized for fixed-dose or concentration-controlled therapy. All patients received a quadruple immunosuppressive regimen consisting of basiliximab induction therapy, CsA, prednisone and MMF. Based on six measurements of an abbreviated MPA-AUC, the MMF dose was adjusted to aim for a target MPA- AUC of 40 mg h/l. MMF dose adjustments were calculated by a computer program (available at using a Bayesian estimator. Treatment failure (a composite of death, graft loss, acute rejection and MMF discontinuation) was the primary endpoint. At 12 months the concentration-controlled group had significantly less treatment failures (19/65 vs. 31/65 in fixed-dose patients; p = 0.03), and less biopsy-proven acute rejections (BPARs) (5/65 vs. 16/65; p = 0.01). There was not an increased incidence of adverse events in the concentration-controlled patients, with the exception of more herpes virus infections. The second, fixed-dose versus concentration controlled (FDCC), study was a much larger study, including 901 renal transplant recipients from 19 different countries (22). In the FDCC study the patient population was more diverse, with both adult and pediatric patients, with about half of the patients on CsA and the other half on tacrolimus cotherapy and with induction therapy used in 46% of patients. The study design was quite similar, with adjustment of MMF dose in the concentrationcontrolled patients based upon six measurements of MPA- AUC in the first 12 months after transplantation, aiming for a target MPA-AUC of 45 mg h/l. MMF dose adjustments in the FDCC study were not calculated by a web-based computer program nor with a Bayesian estimator, but were calculated by the investigators, assuming dose proportionality. Also in FDCC treatment failure (a composite of death, graft loss, acute rejection and MMF discontinuation) was the primary endpoint. The incidence of treatment failure in the FDCC study was identical in fixed-dose and concentration-controlled patients (25.7% vs. 25.6%). Also incidence of BPAR was not different (15.5% vs. 14.9%) between the two treatment arms. Although in the FDCC study a benefit of TDM was not demonstrated, a significant relationship between MPA-AUC on day 3 and incidence of BPAR was confirmed. This difference in the outcome of the two randomized studies is remarkable, given the similar study designs. One of the potential causes for the difference in the outcome between the APOMYGRE and the FDCC studies is the method used for TDM. In the French study, investigators entered the results of locally measured MPA plasma concentrations into a web-based program, which calculated MPA-AUC using Bayesian forecasting, and forwarded an advice for a new dose to the investigator. Compliance by the physicians with the dosing recommendations was as high as 85%. In the FDCC study the investigators had to calculate AUC themselves using a limited sampling American Journal of Transplantation 2009; 9:

4 van Gelder algorithm, and then had to calculate the new MMF dose using a (dose-proportional) formula. Especially for large dose increases, compliance of the investigators was far lower (48%) compared to the APOMYGRE study. It seemed that there was a reluctance of the FDCC investigators to push up the dose from 2 g daily to doses as high as 3 or 4 g daily in the first weeks after transplantation. Whether the better compliance with the study protocol in APOMYGRE was due to the use of the web-based program or to a much smaller group of dedicated investigators is unclear. The difference in compliance is reflected in the MMF doses used in the concentration-controlled patients. The mean MMF daily dose in concentration-controlled patients in the APOMYGRE study reached a maximum of 2969 mg at the fourth postoperative week, while in FDCC the (cyclosporine treated) concentration-controlled patients had their highest mean MMF daily dose of 2325 mg at week 4. The more pronounced dynamics of the MMF dose in the APOMYGRE study resulted in larger differences in MPA exposure between the two groups, in more patients within the therapeutic window and in a significantly better outcome in the concentration-controlled patients. Nevertheless, even in the APOMYGRE study, and despite the use of a Bayesian approach, on day 14 no less than 32% of the patients had a MPA-AUC below the lower threshold of 30 mg h/l. Within-patient variability in the PKs of MPA may explain why, even in concentration-controlled patients, adequate MPA exposure is not always guaranteed. This is an understudied topic, as is the presumed dose proportionality for MMF. Especially in patients with initial poor renal function, MPA concentrations may not be linearly related to the MMF dose. How do we continue after publication of APOMYGRE and FDCC? Although it was expected that the randomized trials would give the final answer, and that after these trials it would be evident if TDM for MMF is of benefit or not, the reality is that the publication of the two studies has not had much impact on patient management. Although this cannot be supported by any hard data, it seems that only few centers have changed their policy based on these studies. From a third randomized trial (Opticept), the results have not been published yet, but interim results have been shown at the congress of the International Transplantation Society in Sydney (23). In Opticept, concentration-controlled MMF combined with reduced level calcineurin inhibitor was found to be noninferior to concentration-controlled MMF combined with standard level calcineurin inhibitor and noninferior to fixed-dose MMF combined with standard level calcineurin inhibitor. What the randomized trials have clearly shown is that early adequate exposure to MPA in the first week after transplantation is important. With TDM it will be hard to improve MPA exposure this early, and the use of an increased starting dose would be a better approach. Studies are ongoing, with varying loading periods of 2 6 weeks ( NCT ). The increased dose will certainly avoid underexposure to MPA in higher proportions of patients at an early stage after transplantation. It remains to be shown that with higher starting doses, efficacy will really be better. The ongoing trials will tell us. Unavoidable will be that due to loading doses also more patients will be exposed to MPA-AUCs exceeding the upper threshold of the therapeutic window. TDM could help to identify these patients, allowing for more rapid tapering of the MMF dose, and possibly avoiding toxicity. The use of intravenously (iv) administered MMF will not solve the problem of early underexposure. Pescovitz et al. showed that MPA-AUC was only 20% higher in i.v. treated patients, reflecting the high bioavailability of MMF (24). In contrast to the accumulating evidence supporting the importance of early MPA exposure, there is a lack of supportive data for the relevance of MPA measurement in long-term patient management. In part this is caused by the low incidence of acute rejection after the first 3 months. Another reason is the paucity of studies investigating the concentration effect relationship beyond the first posttransplant year. Conclusion The repetitively shown concentration effect relationship for MPA, and the vast between-patient variability in MPA concentrations found in patients on standard dose MMF therapy, for some centers has provided enough evidence to implement TDM for MMF for daily clinical practice. The publication of two randomized trials investigating the added benefit of TDM for MMF in renal transplant patients has not had much impact on patient management. Underexposure to MPA in the first week after transplantation is highly predictive of developing subsequent acute rejections and an increased MMF starting dose may be the way to go. Possibly, also with this approach TDM can be helpful, especially in identifying patients with MPA overexposure, in whom dose should be reduced. Within-patient variability in the PKs of MPA and dose proportionality for MPA should be studied in more detail and may help to better understand how to adjust MMF dose based on MPA plasma concentrations. Conflict of Interest Teun van Gelder has received honoraria, and lecture fees, as well as a research grant from F. Hoffmann-La Roche Ltd. References 1. Knight SR, Morris PJ. Does the evidence support the use of mycophenolate mofetil therapeutic drug monitoring in clinical 1498 American Journal of Transplantation 2009; 9:

5 Mycophenolate Blood Level Monitoring practice? A systematic review. Transplantation 2008; 85: de Winter BC, van Gelder T, Glander P et al. Population pharmacokinetics of mycophenolic acid : A comparison between enteric-coated mycophenolate sodium and mycophenolate mofetil in renal transplant recipients. Clin Pharmacokinet 2008; 47: van Hest RM, van Gelder T, Bouw R et al. Time-dependent clearance of mycophenolic acid in renal transplant recipients. Br J Clin Pharmacol 2007; 63: van Hest RM, van Gelder T, Vulto AG, Mathot RA. Population pharmacokinetics of mycophenolic acid in renal transplant recipients. Clin Pharmacokinet 2005; 44: Le Guellec C, Bourgoin H, Büchler M et al. Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in stable renal transplant patients. Clin Pharmacokinet 2004; 43: van Hest RM, Mathot RA, Pescovitz MD, Gordon R, Mamelok RD, van Gelder T. Explaining variability in mycophenolic acid exposure to optimize mycophenolate mofetil dosing: A population pharmacokinetic meta-analysis of mycophenolic acid in renal transplant recipients. J Am Soc Nephrol 2006; 17: Hesselink DA, van Gelder T. Genetic and nongenetic determinants of between-patient variability in the pharmacokinetics of mycophenolic acid. Clin Pharmacol Ther 2005; 78: Van Gelder T, Hilbrands LB, Vanrenterghem Y et al. A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation. Transplantation 1999; 68: Weber LT, Shipkova M, Armstrong VW et al. The pharmacokineticpharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002; 13: Ekberg H, Grinyó J, Nashan B et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: The CAESAR Study. Am J Transplant 2007; 7: Atcheson BA, Taylor PJ, Mudge DW et al. Mycophenolic acid pharmacokinetics and related outcomes early after renal transplant. Br J Clin Pharmacol 2005; 59: Dost D, van Leerdam ME, van Dekken H et al. Crohn s-like enterocolitis associated with mycophenolic acid treatment. Gut 2008; 57: Heller T, van Gelder T, Budde K et al. Plasma concentrations of mycophenolic acid acyl glucuronide are not associated with diarrhea in renal transplant recipients. Am J Transplant 2007; 7: Pisupati J, Jain A, Burckart G et al. Intraindividual and interindividual variations in the pharmacokinetics of mycophenolic acid in liver transplant patients. J Clin Pharmacol 2005; 45: Tredger JM, Brown NW, Adams J et al. Monitoring mycophenolate in liver transplant recipients: Toward a therapeutic range. Liver Transpl 2004; 10: Meiser BM, Pfeiffer M, Schmidt D et al. Combination therapy with tacrolimus and mycophenolate mofetil following cardiac transplantation: Importance of mycophenolic acid therapeutic drug monitoring. J Heart Lung Transplant 1999; 18: Yamani MH, Starling RC, Goormastic M et al. The impact of routine mycophenolate mofetil drug monitoring on the treatment of cardiac allograft rejection. Transplantation 2000; 69: DeNofrio D, Loh E, Kao A et al. Mycophenolic acid concentrations are associated with cardiac allograft rejection. Heart Lung Transplant 2000; 19: Neumann I, Fuhrmann H, Fang IF, Jaeger A, Bayer P, Kovarik J. Association between mycophenolic acid 12-h trough levels and clinical endpoints in patients with autoimmune disease on mycophenolate mofetil. Nephrol Dial Transplant 2008; 23: de Winter BC, van Gelder T. Therapeutic drug monitoring for mycophenolic acid in patients with autoimmune diseases. Nephrol Dial Transplant 2008; 23: Le Meur Y, Büchler M, Thierry A et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant 2007; 7: van Gelder T, Silva HT, de Fijter JW et al. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: The fixed-dose concentration-controlled trial. Transplantation 2008; 86: Bloom R, Kaplan B, Meier-Kriesche HU et al. Opticept trial: Efficacy and safety of monitored MMF in combination with CNI in renal transplantation at 1 and 2 years. Transplantation 2008; 86(Suppl): 301 (Abstract 862). 24. Pescovitz MD, Conti D, Dunn J et al. Intravenous mycophenolate mofetil: Safety, tolerability, and pharmacokinetics. Clin Transplant 2000; 14: American Journal of Transplantation 2009; 9: