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Patients on standard-dose mycophenolate mofetil (MMF) therapy show considerable between-patient variability in pharmacokinetic parameters (1). This variability is attributable to factors that influence exposure to MMF, such as patient renal function, serum albumin levels, and concomitant medications such as cyclosporine that inhibit enterohepatic recirculation of the active metabolite of MMF, mycophenolic acid (MPA) (2). This variability is clinically relevant because higher plasma concentrations of MPA are correlated with reduced risk of acute rejection after kidney transplantation (3). These findings have suggested that individualizing the dose regimen of MMF may further improve clinical outcomes compared with a standard 1000 mg twice daily regimen (4, 5).
The potential for therapeutic drug monitoring of patients receiving MMF in improving clinical outcomes was first demonstrated in a randomized, concentration-controlled trial in renal transplant patients receiving MMF, cyclosporine and corticosteroids, (6) and in studies in pediatric patients (7, 8). Recommendations describing MMF therapeutic drug monitoring have been published, although at the start of the study the feasibility of implementing a concentration controlled approach had not been demonstrated (9, 10). Also, in view of the cost and effort involved in performing therapeutic drug monitoring, more evidence for the validity of a dose individualization approach is needed. A randomized, multicenter, prospective trial was designed to investigate the added value of therapeutic drug monitoring of MPA by comparing fixed-dose MMF treatment with concentration-controlled treatment in de novo kidney transplant recipients.
The MPA area under the concentration–time curve (AUC) was selected as the pharmacokinetic parameter for drug monitoring because it is more strongly correlated with acute rejection than the predose plasma concentration (3); however, determination of AUC is impractical to perform in routine clinical practice, thus a limited sampling strategy was used in this study.
Adult and pediatric patients, aged 2 years or older, who were to receive an ABO-compatible single-organ kidney transplant from a living donor (related or unrelated) or from a deceased donor were eligible for the study. We excluded those receiving immunosuppressive therapy (except steroid treatment) within the preceding 28 days except for pretransplant immunosuppressive medication (up to 48 hr before transplantation), which included perprotocol MMF treatment in all patients within 6 hr before transplantation; those with active or a history of malignant disorders (apart from localized nonmelanotic skin cancer); those with serological evidence of infection with HIV or hepatitis B, active infections, hematological abnormalities (white blood cell count<2500/mm3, platelet count<75,000/mm3, or hemoglobin<9.7 g/dL for adults receiving erythropoietin, <6.6 g/dL for adults not receiving erythropoietin or for pediatric patients), panel reactive antibodies above 50% within 6 months before study entry, cold ischemia time greater than 48 hr, active peptic ulcer disease, liver cirrhosis or clinical evidence of portal hypertension or other indication of moderate or severe liver disease; pregnant women, nursing women, and women who did not agree to use adequate contraception. All patients selected provided written informed consent according to the Declaration of Helsinki. The study protocol was approved by the ethics committees of all participating centers and the relevant authorities in the participating countries.
Study Design and Procedures
This 12-month, prospective, randomized, open-label, parallel-group study was performed in 67 centers in 19 countries in Europe, South America, Canada, Asia, and Australia between May 2003 and April 2006. All eligible participants from each study center were randomized centrally, through an automated telephone system, in a one-to-one ratio to receive fixed-dose MMF or an MMF dose based on MPA plasma concentration measurements (the concentration-controlled group). Randomization was performed in random permuted blocks of eight patients per center.
All patients had to start with MMF within the first 6 hr before transplantation. In patients with a living donor, immunosuppressive treatment was also allowed for 48 hr before transplantation; patients received a single oral dose of MMF (1000 mg in adults [regardless of ethnicity], 600 mg/m2 in pediatric patients). In the fixed-dose group, adults received 1000 mg twice daily and pediatric patients received 600 mg/m2 twice daily for the first 30 days after transplantation. Thereafter, the patients received a center-defined maintenance dose for the remainder of the 12-month study period. Dose adjustments were allowed based on clinical events. In the concentration-controlled group, patients started MMF therapy using the same dose as fixed-dose patients. MPA plasma concentrations were measured at three time points: before (predose concentration), and 30 and 120 min after oral MMF administration. The MPA abbreviated AUC from 0 to 12 hr (AUC0–12) was calculated from these three MPA concentrations using four different algorithms, which were for adult patients on tacrolimus (11) or cyclosporine (unpublished data), or for pediatric patients on tacrolimus (12) or cyclosporine (13). The main reasons for choosing the limited sampling MPA-AUCs with time points 0, 30, and 120 min were as follows: (1) a 2-hr sampling period is more patient friendly than a 4- or 6-hr time frame; (2) we had validated algorithms for all of the following four patient groups: adults on CsA, adults on tacrolimus, children on CsA, children on tacrolimus; and (3) in some of the participating hospitals, patients were included in more than one of the mentioned four patient groups; to avoid confusion we picked the same time points for blood sampling for all four patient groups. MPA concentrations were measured locally using immunoassay (EMIT, DadeBehring, Newark, DE) in 53% of patients or high-performance liquid chromatography in 47% of patients. To rapidly implement dose changes after AUC measurements, centers were asked to aim for short turn-around times for MPA measurements. All centers were required to participate in the proficiency-testing scheme organized by the Analytical Unit at St George's, University of London, London, UK (14). Six pharmacokinetic assessments, each consisting of an abbreviated AUC0–12, were performed: on days 3 and 10; week 4; and months 3, 6, and 12. Based on the relationship found by Hale et al. (3) the target MPA-AUC range was 30 to 60 mg hr/L, with dose-adjustments calculated by the investigators to achieve a target MPA AUC of 45 mg hr/L. The midpoint of the target was used for the dose adjustment as we recognized that the levels that would be achieved would range on either side of the midpoint to a varying degree. Details of the dose adjustments are available in the Supplemental Appendix appearing online only. MMF dose-adjustments were proportional to the desired change in MPA exposure, with the following formula: new MMF dose=(desired AUC/present AUC)×present dose. The maximum MMF dose was 2500 mg twice daily (1250 mg/m2 in pediatric patients) at any time, with maximum treatment duration at this dose of 4 weeks. In the fixed-dose group, pharmacokinetic assessments were performed at the same time points after transplantation. Investigators were blinded to the results of the MPA assay in fixed-dose patients until study completion.
Concomitant immunosuppressive therapy consisted of a calcineurin inhibitor (cyclosporine or tacrolimus, at blood concentrations defined by the center protocol from the onset of the study) and corticosteroids. Other immunosuppressive drugs, such as azathioprine, everolimus, and sirolimus were prohibited. Induction therapy with antibodies was permitted. Standard calcineurin inhibitor (CNI) and corticosteroid tapering regimens were left to the discretion of the investigators.
The primary efficacy endpoint was the proportion of patients reaching treatment failure, a composite endpoint of biopsy-proven acute rejection (BPAR), graft loss, death, or discontinuation of MMF therapy (whichever was reached first), by 12 months after transplantation. All clinically apparent episodes of acute rejection had to be confirmed by core biopsy. All biopsy samples were assessed locally by a pathologist, and rejection was classified according to the revised Banff grading system (15). Biopsy-proven acute rejection was defined as any histologically confirmed episode for which a Banff score of 1 (mild, grades IA and IIA), 2 (moderate, grades IB and IIB), or 3 (severe, grade III) was recorded.
The secondary efficacy endpoints included the cumulative proportion of patients experiencing BPAR or presumed acute rejection, time to first acute rejection, graft loss, or death. Secondary safety objectives were the incidence of opportunistic infections and malignancies, renal function, and occurrence of adverse events. There were five prespecified adverse events that were of particular interest for this study: diarrhea (defined as more than four loose stools daily), leukopenia (defined as a total leukocyte count below 3.0×109/L), thrombocytopenia (defined as a total thrombocyte count below 100×109/L), anemia (defined as a hemoglobin level below 11.3 g/dL after day 28), and weight loss (defined as a loss of >10% of the body weight at transplantation). Pharmacokinetic endpoints included a comparison of MPA exposure between the fixed-dose and concentration-controlled groups and between the subsets of cyclosporine- and tacrolimus-treated patients. The relationship between MPA exposure and efficacy and toxicity was specified in the statistical analysis plan.
Sample size was calculated on the basis of the expected frequency of the primary endpoint, which was 40%, and a 10% difference between treatment groups in the primary endpoint rate was considered a meaningful margin of superiority. For an 80% power to detect a statistically significant (P<0.05) reduction, 376 patients per treatment arm had to be randomized. To account for a predicted 20% drop-out rate, a total of 900 patients were required.
For the analysis of both efficacy and safety the intention-to-treat population was used, which included all randomized patients who were treated with at least one dose of MMF. Numerical data are presented as means±SD. The Cochran-Mantel-Haenszel test for differences between treatment groups, stratified by center, was used for treatment failure.
Between-group differences in the incidence of prospectively recorded adverse events were compared using the Fishers exact test. The probability of BPAR as a function of MPA AUC, as assessed at each of the first five sampling time points, was analyzed for rejections in the first month (days 3 and 10) or in the entire first year (for all five time points) using logistic regression. The incidence of the primary outcome in the two arms of the study was also analyzed in the retrospectively defined perprotocol population, defined as all patients in whom at least four of the first five AUC values were obtained, and in whom the first dose adjustment (after the determination of AUC on day 3) was performed according to protocol. In the analysis of secondary endpoints no adjustment in the level of significance was made to account for multiple comparisons. Data were entered into a web-based electronic database. Study monitoring was performed according to Good Clinical Practice guidelines. The statistical analysis was carried out by the Clinical Research Organization, Quintiles.
A total of 901 patients were randomly assigned to the concentration-controlled (n=449) or fixed-dose (n=452) groups (Fig. 1). There were no apparent differences between the two treatment groups in any demographic or baseline characteristic (Table 1). Of the 901 patients in the study, 62 were younger than 18 years at the day of transplantation (31 in each group).
During the study, 54% of patients received cyclosporine and 46% received tacrolimus. Induction therapy with antibodies was used in 46% of patients and 74% of patients received a kidney from a deceased donor.
The proportion of patients reaching the composite endpoint of treatment failure in the concentration-controlled group was 115 of 449 patients (25.6%) and in the fixed-dose group was 116 of 452 (25.7%); P=0.81 (Table 2). There was no significant between-group difference for each component of the composite endpoint (data not shown). The incidence of treatment failure in the concentration-controlled group was not different from that in the fixed-dose group in patients receiving induction antibody therapy (23.9% vs. 27.5%). We have repeated the analysis for the primary outcome of treatment failure for white patients separately. Similar to the full analysis set we found no difference in the incidence of treatment failure between concentration-controlled and fixed-dose patients: 102 of 373 (27.3%) vs. 97 of 365 (26.6%). Overall, 1-year patient and graft survival were excellent (97.1% and 94.8%, respectively), and similar in both arms of the study, as were between-group differences for other secondary efficacy endpoints (Table 2).
The total number of treatment-emergent adverse events, patients with at least one adverse event or one serious adverse event, was similar in the two study groups (Table 3). The incidence of diarrhea or leukopenia was not different between patients in the concentration-controlled and fixed-dose groups. The proportion of patients in the concentration-controlled and in the fixed-dose groups with at least one opportunistic infection (132 of 449 vs. 117 of 452 patients) or at least one malignancy (three vs. eight patients) was not significantly different between the two groups.
Patients in the concentration-controlled and fixed-dose groups had similar MPA AUC0–12 values for all time points (Fig. 2). The proportion of patients reaching the target MPA AUC values of 30 to 60 mg hr/L was generally similar between the two groups (Table 4). The turn-around time for MPA-AUC analysis was less than 48 hr, leading to changes in MMF dose within 3 days of drawing blood samples in 92% of patients. There was a significant relationship between early MPA AUC values on day 3 and the incidence of BPAR during the first month (P=0.009) or during the entire first year after transplantation (P=0.006). The relationship of MPA-AUC at day 10 to BPAR between day 10 and month 1 showed a similar trend (P=0.0655). The logistic regression model that included MPA-AUC and time period as explanatory variables indicated that in the total population, during the first year after transplantation, the risk of developing BPAR decreased as MPA-AUC increased (estimate of MPA-AUC effect= −0.0222; 95% CI −0.0228 to −0.0016; P=0.0247). The risk of developing a BPAR in the first year posttransplant was 58 of 308 (18.8%) in patients with a day-3 MPA AUC of less than 30 mg hr/L and was 69 of 517 (13.3%) in those with a corresponding value of more than 30 mg hr/L (P=0.018). We not only found a significant relationship between BPAR and MPA-AUC, but also with predose MPA concentrations (relationship between MPA predose concentration on day 3 and the incidence of BPAR during the first month; P=0.0185). In contrast to the significant correlation between BPAR in the first year and MPA-AUC on day 3, for later time points (day 10, month 1) the correlation was not significant (P values 0.2572 and 0.5588, respectively). This analysis was not performed for MPA-AUC at months 3 and 6, because the low number of BPAR after these time points did not allow meaningful correlation. The cyclosporine subgroup had more patients with MPA AUC below 30 mg hr/L at the first three time points of the study than in the tacrolimus group (Fig. 2). At day 3, only 51.2% of the cyclosporine subgroup had an MPA AUC0–12 above 30 mg hr/L compared with 76.2% of the tacrolimus subgroup. In addition, patients in the cyclosporine subgroup had lower mean MPA AUC12 values (at all six time points) than the tacrolimus subgroup, despite higher mean daily doses of MMF (Table 5).
In an attempt to explain why the concentration-controlled treated patients were not on target MPA exposure more often than fixed-dose patients, a detailed post hoc analysis of the dose adjustments in individual concentration-controlled patients was made. On day 3, 147 of 422 (34.8%) patients in the concentration-controlled group had an MPA AUC of below 30 mg hr/L (with 45.6% [62 of 136] of these patients still below 30 mg hr/L on day 10). In 77 of 147 (52%) patients, dose adjustments after day 3 were absent or insufficient according to the protocol-specified instructions for achieving the target AUC (45 mg hr/L). However, in the perprotocol population, in part defined as those patients in whom the first dose adjustment was carried out correctly, there was no between-group difference in the incidence of treatment failure (data not shown). Finally, mean cyclosporine and tacrolimus concentrations were not significantly different between patients in the concentration controlled and fixed dose group at any of the six time points.
In this prospective, randomized trial, we investigated the added value of therapeutic drug monitoring of MMF in renal transplant patients. Previous pharmacokinetic studies have shown that approximately half of transplant recipients receiving standard-dose MMF in combination with cyclosporine A will have MPA-AUC values below the assumed and accepted therapeutic range of 30 to 60 mg hr/L in the early posttransplant period (10). In designing the current study, it was anticipated that individualizing the MMF dose regimen based on target MPA exposure would result in a higher proportion of patients achieving AUC values within the 30 to 60 mg hr/L therapeutic window in the concentration-controlled group compared with the fixed-dose group, and that this would translate into improved clinical outcome. Unexpectedly, this was not observed, and mean MPA AUC values, and the proportion of patients achieving AUC values within the therapeutic range of 30 to 60 mg hr/L in the current study, was similar in the concentration-controlled and fixed-dose groups. Given the lack of difference in MPA exposure, differences in efficacy and safety outcomes between treatment arms could not be expected, and were not observed.
Nevertheless, there are still important things we can learn from this study. This study confirmed the previously reported MPA exposure/response relationship (3, 7). There was a significant relationship between exposure early after transplantation and BPAR during the first month (days 3 and 10 MPA-AUC) or during the first year (day 3 MPA-AUC) after transplantation, highlighting the importance of reaching target concentrations as early as possible. Similar to the findings in another study, (16) an MPA AUC below 30 mg hr/L on day 3 posttransplant correctly identified 79% of patients suffering acute rejection within 3 months of transplantation. In this study, the proportion of concentration-controlled patients with an MPA AUC value below 30 mg hr/L was 34.8% on day 3, with little improvement by day 10 (45.6% of these patients still below 30 mg hr/L). Remarkably, we not only found a significant relationship between BPAR and MPA-AUC, but also with predose MPA concentrations. There is no doubt that monitoring predose concentrations is much more practical than an abbreviated AUC-based approach. The approach suggested by Borrows et al. (17) may therefore also be of practical importance. The lack of a significant relationship between MPA-AUC and BPAR at later time points (month 1 and beyond) suggest that the value of dose adjustments based on drug concentrations is limited to the first month. However, we would emphasize that in this study conventional dose CNI therapy was used. In regimens with reduced dose CNI the importance of reaching adequate MPA exposure may increase and may also be relevant at later time points (18).
Overall, about one third of patients had MPA exposure below 30 mg hr/L up to day 10, suggesting that improved efficacy might have been achieved if the MPA exposure reached the therapeutic range earlier. As anticipated, MPA exposure was lower in the CsA subgroup compared with the tacrolimus subgroup, with approximately 50% of CsA recipients failing to reach the 30 mg hr/L target exposure. Exposure in the first few days after transplant is determined by initial dosing, whereas therapeutic drug monitoring has the potential to affect exposure later on. For a drug with the pharmacokinetics of MPA started on the day of transplantation, a first measurement of exposure will not yield meaningful results until after four to six doses. Thus, it is likely to take until at least the end of the first week before a dose change results in a new steady-state concentrations of MPA. We propose that adult patients treated with tacrolimus begin with an MMF starting dose of 1000 mg twice daily, producing an acceptable MPA exposure in approximately 80% of patients. In patients treated with cyclosporine, a 1500 mg twice daily starting dose would be more appropriate. In these patients, assessing MPA concentrations after 1 or 2 weeks would identify those patients in whom the MMF dose could be safely tapered.
We also showed that although MPA AUC at the first time point (day 3) was below target in a substantial proportion of the patients, many investigators did not increase the MMF dose adequately to reach the targeted exposure. As a result, the proportion of patients reaching the target exposure did not improve as rapidly as might have been expected using therapeutic drug monitoring, and as had been demonstrated using a computer simulation model (19). Apparently the investigators, many of whom have used this drug in a maximum dose of 2 g for the last 10 years, were not comfortable increasing the MMF dose much beyond the standard dosage (1000 mg twice daily) based on one or two abbreviated AUC measurements. However, the lack of a difference between treatment arms in the incidence of treatment failure in perprotocol population demonstrates that the negative outcome of this study cannot be fully explained by failure to comply with the proposed dose adjustments alone. Also, the relatively long turn-around time for MPA-AUC analysis in some centers cannot explain the lack of difference between the concentration-controlled and the fixed-dose group, as the 7-day interval between the first and second AUC measurement would still allow for attainment of target AUC despite a few days delay. Of note, the definition of the perprotocol population was defined only by the dose correction made on day 3 and not on subsequent dose corrections and did not take into account whether the target AUC was actually achieved.
The relationship between pharmacokinetic variables and safety outcomes has thus far been inconsistent and difficult to ascertain (10). Adverse events that could be ascribed to MPA, such as leukopenia, infections, and diarrhea, have multiple causes. Only large data sets would be capable of detecting specific causes for these adverse events. In another concentration-controlled trial (3), gastrointestinal toxicity was dose-related. In this study, diarrhea was not more frequent in the concentration-controlled group, despite higher MMF mean daily doses in this group (data not shown).
A similar study to ours was conducted in France, (20) in which a more homogeneous patient population of adult renal transplant recipients received MMF, cyclosporine, corticosteroids, and basiliximab. Although a smaller study (n=130), there was a significantly lower incidence of BPAR in the concentration-controlled than fixed-dose group (5 vs. 16, P=0.02), and importantly a notably higher mean MPA exposure during the first few months of treatment. An important difference with our study is that in the French study, locally measured MPA concentrations were entered into a web-based consulting service (www.chu-limoges.fr/stp/stpacces.htm) (21), and a new dose recommendation was calculated using a Bayesian forecasting computer program and forwarded to the treating physician. The feasibility and success of this approach had not been demonstrated previously. The observed difference in compliance with the dose-adjustment protocol between the two studies is remarkable and forms an important lesson for future studies investigating the contribution of therapeutic drug monitoring for any drug.
In summary, this prospective, randomized trial did not show a benefit of therapeutic drug monitoring for MMF, in part, because of nonadherence to required early dose increments. Nonetheless, the relationship between exposure, especially early exposure on day 3, and efficacy during the first year after transplantation was confirmed. We propose that clinical outcomes might be improved if the starting dose of MMF is 1 g twice daily when coadministered with tacrolimus and 1.5 g twice daily with cyclosporine. Therapeutic drug monitoring, with correct dose adjustments, could still have a positive effect on outcome. Future studies in this area should carefully assess what can be done to assist physicians in adhering to a concentration-controlled approach.
The authors thank Wilson Sama and Neva Coello (both from BIOP; Basel, Switzerland) for guidance with statistical analysis and Richard Glover for editorial assistance.
T. van Gelder and R. Mamelok participated in all stages of the study, data interpretation, and preparation of the report. D. Kuypers, Y. Le Meur, M. Oellerich, D. Holt, B. Tönshoff and P. Keown contributed to study design and were members of the study steering committee. H. Tedesco Silva, H. de Fijter, K. Budde, D. Kuypers, G. Tyden, A. Lohmus, C. Sommerer, A. Hartmann, Y. Le Meur, B. Tönshoff, P. Keown, and S. Campbell contributed to recruitment and patient management, and critically reviewed the manuscript. All authors have approved the final report.
Without the continued support of the patients, investigators and nursing staff, this study would not have been possible, and we thank the following investigators: Australia: Irish Ashley, Perth; Campbell Scott, Brisbane; Kanellis John, Clayton; Goodman David, Melbourne; Trevillian Paul, New Lambton; Moody Henry, Nedlands; Walker Rowan, Melbourne;Austria: Pohanka Erich, Vienna; Holzer Herwig, Graz;Belgium: Kuypers Dirk, Leuven;Brazil: Tedesco Silva Jr. Helio, Säo Paolo;Canada: Keown Paul, Vancouver;China: Zhou Peijun, Shanghai; Lu YiPing, Sichuan;Denmark: Jensen Jorgen, Odense;Estonia: Lohmus Aleksander, Tartu;France: Vialtel Paul, Grenoble; Rifle Gerard, Dijon; Le Meur Yann, Limoges; Delahousse Michel, Suresnes; Bouissou Francois, Toulouse; Kessler Michele, Nancy-Brabois; Thervet Eric, Paris; Dehennault Maud, Lille; Merville Pierre, Bordeaux; Noel Christian, Lyon; Soulilou Jean-Paul, Nantes; Charpentier Bernard, Kremlin Bicêtre; Rostaing Lionel, Toulouse; Pouteil-Noble Claire, Lyon; Rondeau Eric, Paris;Germany: Arns Wolfgang, Köln; Neumayer Hans, Berlin; Pisarski Przemyslaw, Freiburg; Tönshoff Burkhard, Heidelberg; Lopau Kai, Wuerzberg; Schmidt Jan, Heidelberg;Lithuania: Zelvys Arunas, Vilnius;Netherlands: De Fijter Johan, Leiden; van Gelder Teun, Rotterdam;Norway: Hartmann Anders, Oslo;Poland: Rubik Jacek, Warsaw; Senatorski Grzegorz, Warsaw;Spain: Vila Ana, Barcelona; Garcia Meseguer, Madrid; Marques Vidas Maria, Madrid; Luna Huerta Enrique, Badajoz; Pallardo Luis, Valencia; Plaza Juan Jose, Madrid; Osuna Antonio, Granada; Govantes Miguel Angel Gentil, Sevilla; Villafruela Sanz Juan Jose, Madrid; Del Castillo Domingo, Cordoba; Puig Jose Maria, Barcelona; Alarcon Zurita Antonio, Palma de Mallorca; Romero Rafael, Santiago de Compostela;Sweden: Wahlberg Jan, Uppsala; Tyden Gunnar, Huddinge; Ekberg Henrik, Malmö;Taiwan: Po-Huang Lee, Taipei;UK: Powis Stephen, London; MacPhee Ian, London; Pattison James, London;Venezuela: Arminio Anabela, Caracas; Rodriguez Candelaria, Caracas; Rosales Beatriz, Maracaibo.
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