Enteric-coated mycophenolate sodium in de novo pediatric renal transplant patients

Pediatr Nephrol (2009) 24:395–402 DOI 10.1007/s00467-008-1031-7 ORIGINAL ARTICLE Enteric-coated mycophenolate sodium in de novo pediatric renal transplant patients Patrick Niaudet & Marina Charbit & Chantal Loirat & Anne-Laure Lapeyraque & Michel Tsimaratos & Mathilde Cailliez & Michel Foulard & Maud Dehennault & Pierre Marquet & Kamel Chaouche-Teyara & Djamila Lemay Received: 4 April 2008 / Revised: 15 August 2008 / Accepted: 18 August 2008 / Published online: 5 November 2008 # IPNA 2008 Abstract Data on the use of enteric-coated mycophenolic acid (EC-MPS) in pediatric transplantation cases are scarce. We undertook a 12-month, multicenter, open-label pilot study in which 16 de novo renal transplant patients aged 5–16 years received EC-MPS with cyclosporine A microemulsion (CsA-ME), steroids, and anti-interleukin-2 receptor antibody induction. The mean dose of EC-MPS was 916±93 mg/m2 per day during weeks 1–2, 810±193 mg/m2 per day during months 3–6, and 827±153 mg/m2 per day during months 6–12. The mean CsA C2 level exceeded target range up to month 6 post-transplant. Efficacy failure (biopsy-proven acute rejection, graft loss, death or loss to follow-up) occurred in two patients: one patient with P. Niaudet (*) : M. Charbit Pediatric Nephrology, Necker Hospital, 161 rue de Sevres, 75743 Paris, Cedex, France e-mail: niaudet@necker.fr C. Loirat : A.-L. Lapeyraque Pediatric Nephrology, Robert Debré Hospital, 75019 Paris, Cedex, France M. Tsimaratos : M. Cailliez Pediatric Nephrology, AP-HM Timone-Enfants Hospital, 13385 Marseille, Cedex, France M. Foulard : M. Dehennault Pediatric Nephrology, Hôpital Jeanne de Flandre, 59037 Lille, France P. Marquet INSERM U850, CHU de Limoges, Université de Limoges, Limoges, France K. Chaouche-Teyara : D. Lemay Novartis France SAS, 92506 Rueil-Malmaison, Cedex, France primary non-function underwent nephrectomy, and one patient experienced biopsy-proven acute rejection (Grade 1B, day 344) following EC-MPS dose reduction. There were no deaths. Creatinine clearance (Schwartz) was 103± 30 mL/min per 1.73 m2 at month 6 and 100±16 mL/min per 1.73 m2 at month 12. The majority of adverse events were mild or moderate (101/126, 80.2%). In this pilot study, EC-MPS 450 mg/m2 administered twice daily with CsA, steroids, and interleukin-2 antibody induction resulted in a low rate of rejection with good renal function in a pediatric population. However, a larger, controlled trial is required to confirm these results. Keywords Cyclosporine A . EC-MPS . MPA . Mycophenolic acid . Renal function . Renal transplantation Introduction Mycophenolic acid (MPA) therapy has become a mainstay of immunosuppression following convincing evidence of an efficacy benefit in adult renal transplant recipients [1–3]. In pediatric renal transplantation, a multicenter trial has demonstrated that drug therapy with the mycophenolate mofetil (MMF) formulation of MPA significantly reduces acute rejection and graft loss relative to that in historical controls receiving azathioprine [4]. While randomized trials in the pediatric population are lacking, other prospective [5, 6] and retrospective [7–9] studies in children have consistently shown that MMF therapy is effective in preventing acute rejection and associated with good graft survival rates and an acceptable safety profile. Enteric-coated mycophenolic acid (EC-MPS), in which the release of MPA is delayed relative to MMF [10], has 396 recently become available. The EC-MPS formulation is therapeutically equivalent to MMF in adult de novo renal transplant patients [11], and a large randomized study has shown that patients can be converted from MMF to ECMPS safely without compromising efficacy [12]. Moreover, data on patient-reported outcomes suggest [13] that conversion to EC-MPS can improve or even resolve the gastrointestinal (GI) complications that are frequently observed in MMF-treated patients [14]. In children, the peak concentration of MPA occurs at approximately 2.5 h after the administration of EC-MPS [15] compared to 1–2 h with MMF [16], which is consistent with findings in adult recipients [10]. In patients receiving cyclosporine (CsA), a single-dose pharmacokinetic study of EC-MPS in children aged 5–16 years has demonstrated that 450 mg/m2 of EC-MPS provides similar MPA exposure (area under the curve, AUC) to 600 mg/m2 MMF [15, 16]. There are no data available, however, on the long-term pharmacokinetics of EC-MPS in children. Clinical results in pediatric renal transplant recipients are also limited [17, 18]. In a singlearm study, the conversion of 29 pediatric patients with stable graft function from MMF to EC-MPS was found to be safe and effective with improved GI tolerability [17], a finding that has been reported elsewhere [18], but data in de novo recipients are lacking. The current 12-month, open-label trial was undertaken with the objective of assessing the clinical outcome and efficacy, safety, tolerability and pharmacokinetics of ECMPS in de novo pediatric renal transplant recipients when administered in combination with CsA and steroids. Patients and methods Study design This was a 12-month, multicenter, open-label, single arm pilot study aimed at evaluating the safety, tolerability, and efficacy of EC-MPS with CsA microemulsion [Neoral (CsA-ME)] and steroids with anti-interleukin-2 (IL-2) receptor antibody induction in pediatric de novo renal transplant patients. The trial was undertaken in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice and with the ethical principles laid down in the Declaration of Helsinki [19]. Written informed consent was obtained from the parents of all patients following approval of the study protocol from the Institutional Review Board CCPPRB of Paris-Necker. Study population Patients aged 5–16 years undergoing a primary renal transplant from a deceased or non-human-leukocyte- Pediatr Nephrol (2009) 24:395–402 antigen-identical living donor were eligible for enrollment in this study. Major exclusion criteria were receipt of a multiorgan transplant or a previous non-renal transplant, panel reactive antibodies >50%, cold ischemia time >40 h, antilymphocyte induction therapy, recipient or donor positive for hepatitis C, human immunodeficiency virus (HIV) or hepatitis B surface antigen, abnormal liver function [aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or bilirubin >3 times upper limit of normal], neutrophils <1500/mm3, white blood cell count <2500/mm3, or hemoglobin <6 g/dL. Immunosuppression Induction therapy with an anti-IL-2 receptor antibody induction was administered according to local practice. The EC-MPS was administered orally at a dose of 450 mg/m2 twice daily (b.i.d), with the first dose given within 48 h post-transplantation. The EC-MPS dose could be reduced, or EC-MPS temporarily discontinued, in the event of leukopenia (<4000/mm3), neutropenia (<1500/mm3), or severe adverse events at the discretion of the investigator. The CsA-ME therapy was initiated pre-transplant or within 48 h of transplantation according to local practice, at an initial dose of 10–12 mg/kg per day. The dose was subsequently adjusted based on CsA C2 level (i.e. blood concentration 2 h post-dose), targeting the following ranges: 1100–1300 ng/mL during month 1, 800–1000 ng/mL during months 2–3, and 600–800 ng/mL thereafter. Intravenous or oral steroids were administered within 24–48 h posttransplantation at a dose of 60 mg/m2 per day (<80 mg/day) prednisone or equivalent, adjusted to 30–60 mg/m2 per day during days 1–30, 15–30 mg/m2 per day during days 30–60, and 7.5–15 mg/m2 per day during days 60–180. From month 6 to month 12, steroids were administered at 7.5 mg/m2 every day, or every second day at a dose of 18.75 mg/m2 during months 7–8 and <10 mg/m2 during months 9–12. Within these limitations, steroid dosing was as per local practice, but the steroid regimen was identical for all patients within each center. Records of the study medication used, dosages administered, and intervals between visits were maintained throughout the study, and patients were asked to return all unused medication at the end of the study. Renal biopsy was performed prior to the initiation of antirejection or within 48 h of starting treatment. Biopsies were graded locally by pathologists according to Banff 1997 criteria [20]. Acute rejection was treated according to local practice. The protocol stipulated that in all cases in which the donor was positive and the recipient was negative for cytomegalovirus (CMV), patients were to receive prophylactic treatment with ganciclovir or valaciclovir for Pediatr Nephrol (2009) 24:395–402 3 months with all patients in a given center receiving the same regimen. In all other cases, pre-emptive therapy or treatment of CMV disease was applied as per local practice. Evaluation Baseline assessments took place 48 h prior to the first dose of EC-MPS. Study visits took place on days 1, 3, 5, 6, 7, 14, and 28 and at months 2, 3, 6, 9, and 12, with day 1 being the day on which the first dose of EC-MPS was given. Adverse events were recorded and graded as mild, moderate, or severe by the investigator. Laboratory tests, including biochemistry, urinalysis, and hematology, were performed at baseline, on days 3 and 7, and during all subsequent study visits. The CsA C2 levels were measured during all study visits from day 3 onwards, with the exception of day 6. Full 12-h MPA pharmacokinetic profiles were recorded on day 28 or month 3 and at month 6, based on the central analysis of blood samples taken predose or at the time EC-MPS dose was taken, and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, and 12 h after EC-MPS dosing. The concentration of MPA and mycophenolic acid glucuronide (MPAG, a major metabolite of MPA) was measured by liquid chromatography coupled with a mass spectrometer using multiple reaction monitoring (LC-MS/MS), and these parameters were used to assess trough level C0), peak concentration Cmax), time to peak concentration (Tmax) and AUC0–12. For patients who discontinued the study prior to month 12, follow-up data were obtained at months 3, 6, 9, and 12 where possible. Study endpoints and analysis The primary endpoint was treatment failure at months 6 and 12, defined as biopsy-proven acute rejection (BPAR), graft loss, death, or loss to follow-up. Other efficacy endpoints included the incidence of BPAR, graft loss, death and steroid-resistant acute rejection, and renal function at 6 and 12 months (creatinine clearance estimated by the Schwartz formula [21]). The assessment of safety and tolerability was based on the frequency of adverse events and premature discontinuation of study drug due to safety reasons (adverse event, death, graft loss, abnormal laboratory test value) within the first 12 months post-transplant. Efficacy analyses were performed on the intent-to-treat (ITT) population, which comprised all patients who received at least one dose of EC-MPS. Safety and tolerability analyses were performed on the safety population, which consisted of all patients in the ITT population who provided at least one subsequent safety/tolerability assessment. 397 Pharmacokinetic analyses were performed on two occasions: day 28 or month 3, and at month 6. The following MPA and MPAG exposure indices were studied: C0, Cmax, and Tmax, which were directly obtained from the MPA and MPAG plasma concentration profiles, and the inter-dose area under the concentration–time curve (AUC0–12), calculated using the linear trapezoidal rule. When appropriate, dose-standardized AUC0–12 was also considered. Exposure indices at the different monitoring periods were compared using the non-parametric Wilcoxon matched-pairs signed-rank test. The correlations between MPA AUC0–12 and C0 and that between AUC0–12 or AUC0–12/dose at the different periods were studied using linear regression. Results Sixteen patients were recruited at four centers during the period September 2004 to January 2006, with the last patient visit taking place in January 2007. These patients comprised the ITT and safety populations. Demographics and baseline characteristics are shown in Table 1. All patients received a graft from a deceased donor. Five patients (31%) experienced delayed graft function. There were no major protocol violations. Six patients discontinued both the study treatment and the study, all prior to month 6, due to adverse events (five patients: days 5, 0, 84, 91, and 124, respectively) or withdrawal of consent (one patient: day 15). All patients received anti-IL-2 receptor antibody induction (basiliximab, 15 patients; daclizumab, one patient). The total mean dose of EC-MPS during months 0–12 was 879±130 mg/m2 per day (weeks 1–2, 916±93 mg/m2 per Table 1 Patient demographics and baseline characteristics (safety population, n=16) Patient demographics and baseline characteristics Values Recipient age, years (range) <10 years >10 and <14 years Recipient gender (female/male) Body mass index, kg/m2 (range) End-stage disease leading to transplantation Glomerulonephritis/glomerular disease Renal dysplasia/hypoplasia Nephronophthisis Infantile nephropathic cystinosis Other Donor age, years (range) Cold ischemia time, h 11.4±3.3 (5–16) 5 (31.3%) 6 (37.5%) 11/5 16.9±1.8 (4.4–21.8) 5 (31.3%) 4 (25.0%) 2 (12.5%) 2 (12.5%) 3 (18.8%) 16.8±7.8 (5–29) 19.5±5.7 Continuous variables are shown as mean ± standard deviation (SD) 398 Pediatr Nephrol (2009) 24:395–402 day; weeks 3–4, 929±73 mg/m2 per day; month 2, 883± 126 mg/m2 per day; months 3–6, 810±193 mg/m2 per day; months 6–12, 827±153 mg/m2 per day). Three patients (18.8%) required an EC-MPS dose reduction for ≥5 days. The mean dose of CsA-ME decreased successively from 7.5±2.4 mg/kg per day during the first 2 weeks posttransplant to 5.5±1.4 mg/kg per day during month 3–6 and 4.9 ± 1.7 mg/kg per day during month 6–12, with a corresponding decrease in CsA C2 level (Fig. 1). Mean CsA C2 exceeded target range until month 6. The mean steroid dose during month 1 was 53.2±15.1 mg/day, decreasing to 6.6±3.5 mg/day during months 6–12. Efficacy failure occurred in two patients. There was one graft loss in a patient with primary non-function due to a cold ischemia time of 35 h; this patient required eight dialysis sessions in the first month post-transplantation and then underwent nephrectomy at month 4 after discontinuing the study. One episode of Grade 1B biopsy-proven acute rejection (BPAR) occurred (6.3%) at day 344 posttransplant, which subsequently resolved following treatment with methylprednisolone pulses. Prior to this rejection episode, this patient had been on 1233 mg/m2 per day ECMPS for more than 4 months, but 4 days before the rejection episode, the dose was reduced to 822 mg/m2 per day due to adverse events. This dose reduction coincided with a time when the CsA C2 level was lower than it had been previously (1020, 1092 and 649 ng/mL on days 28, 90, and 344, respectively). It is noteworthy that on days 28 and 180, i.e. 11 and 5 months before rejection, this patient had already received low EC-MPS doses (961 and 422 mg/ m2 per day, respectively) due to adverse events (pyrexia and diarrhea), after which the dose was again increased. Biopsy-proven chronic rejection was observed in three patients (18.8%) by month 12 (one patient with borderline lesions and two patients with Grade II lesions), with a diagnosis of drug-induced toxicity in one case. Creatinine clearance (Schwartz) was 103±30 mL/min per 1.73 m2 at month 6 and 100±16 mL/min per 1.73 m2 at month 12 (Fig. 2). The corresponding values for serum creatinine were 69±19 and 69±13 μmol/L. All 16 patients reported one or more adverse event. There were 126 events in total, of which 77 were graded mild, 24 were graded moderate, and 25 were graded severe (19.8%). The majority of events (n=112) first occurred during months 0–6, with 14 subsequent events reported during months 6–12. The most frequently reported adverse events were pyrexia (eight), decreased blood phosphorus (six), diarrhea (six), hypertension (six), complications of the transplanted kidney (one primary non-function, four delayed graft function), abdominal pain (four), anemia (four), and constipation (four). Gastrointestinal disorders were reported in six patients, with a suspected relationship to EC-MPS in all six patients. There were 26 serious adverse events in ten patients, the most frequent of which were pyrexia (seven), anemia (two), neutropenia (two), leukopenia (two) and diarrhea (two). Fourteen patients (87.5%) experienced one or more infection, 87.3% of which were mild or moderate (48/55). Seven serious infections were reported: pyelonephritis (three), sepsis (two) and BK polyomavirus (one; not specified if in urine or plasma) and CMV disease in one patient who was seropositive prior to transplantation. No malignancies occurred. Twenty-four adverse events in ten patients were suspected by the investigator to be related to EC-MPS, 13 of which were serious adverse events. Five patients were classified as discontinuing EC-MPS due to adverse events, but only in two cases did the adverse events appear likely to be related to EC-MPS (pyrexia/neutropenia/leukopenia and interstitial lung disease/pneumonia). In the other three patients, adverse events were more likely to be related to CsA-ME over-exposure (renal tubular necrosis and two patients with excessive hair growth). Exposure to CsA exceeded the target in the latter three patients. There was an increase in white blood cell count (baseline 6.4±1.2×109/L vs. 9.1±2.0×109/L at month 12, p=0.014) and platelet count (baseline 243±44×109/L vs. 329±58× Fig. 1 Cyclosporine A (CsA) C2 level during months 0–12 (safety population). Shaded areas indicate C2 target ranges. Values are shown as mean ± standard deviation (SD). D Day, M month Fig. 2 Creatinine clearance (Schwartz) during months 0–12 (intentionto-treat population). Values are shown as mean ± standard deviation (SD) Pediatr Nephrol (2009) 24:395–402 399 109/L at month 12, p=0.020) during the 12-month study. There were no other significant differences in hematological parameters or in liver enzymes. Mean blood pressure was 127/76, 113/66, and 110/63 mmHg at day 0 and months 6 and 12, respectively. Pharmacokinetic profiles were available in 13 patients on day 28 or 90, and in eight patients at month 6. The MPA C0 ranged from 0.5 to 48.5 μg/mL (Table 2). No statistically significant difference was found between day 28 and subsequent values. Similarly, Cmax showed a numerical but non-significant decrease over time, with large inter-individual variability [coefficient of variance (CV) 57–100%]. Tmax ranged from 0 to 12 h post-dose, with median values increasing numerically with time posttransplant. The MPA AUC0–12 ranged from 10.5 to 87.1 μg h/mL at day 28 (mean 44.4 μg h/mL; CV 56%) and from 15.2 to 141.0 μg h/mL at months 3–6 (mean 50.1 μg h/mL; CV 64%). Dose-standardized AUC0–12 ranged from 29 μg h/mL per gram to 121 ng h/mL per milligram at day 28 (CV 37%) and from 42 to 392 ng h/mL per milligram at months 3–6 (CV 73%). Numerically, AUC0–12 and AUC0–12/dose were higher at month 3 than at month 6, but the differences were not significant. The MPAG plasma levels were much higher than those of MPA and also less variable, with AUC0–12 ranging between 500 and 3110 μg h/mL on day 28 (CV 57%) and between 233 and 986 μg h/mL at later time points (CV 41%), with a non-significant decrease over time. No significant linear correlation was found between MPA C0 and AUC0–12 at any sampling point (p values between 0.085 and 0.952) or overall (p=0.240). The evening trough level (C12) showed a much better correlation with AUC0–12 from the previous dose, with Pearson correlation coefficients of 0.71 (n=9, p=0.032) on day 28, 0.941 (n=4, p=0.059) on day 90, and 0.265 (n=8, p= 0.525) on day 180 (r = 0.46 overall, n=22, p=0.031). The reproducibility and correlation of dose-standardized AUC0–12 values in individual patients at the different sampling periods could not be studied due to the small population size. The five patients who discontinued study treatment due to adverse events, including the two in whom the adverse events were believed to be related to EC-MPS, were withdrawn before any MPA profile could be studied. Discussion This pilot study provides the first data on the de novo use of EC-MPS with CsA-ME, corticosteroids, and anti-IL-2 receptor antibody induction in children undergoing renal transplantation. In this small population of 16 patients, there was only one episode of mild BPAR throughout the 12-month study, in a patient who had received an EC-MPS dose reduction 4 days previously and in whom the CsA C2 level was lower than previously. The only case of graft loss was due to primary non-function due to prolonged cold ischemia. Five patients discontinued the study due to adverse events, which may reflect the fact that CsA exposure was greater than anticipated and that the ECMPS dose was relatively high. The CsA C2 level exceeded the target range during the first few months post-transplant in the majority of patients, and this may have contributed to the low incidence of biopsy-proven acute rejection (6.3%). The reason why the CsA-ME dose was not reduced adequately to achieve target Table 2 Pharmacokinetic parameters Pharmacokinetic parameters Mycophenolic acid Total daily dose (mg/day) Total daily dose (mg/kg per day) C0 (μg/mL) Cmax (μg/mL) Tmax, h, median (range) AUC0–12 (μg h/mL) AUC0–12/dose (ng h/mL per mg) Mycophenolic acid glucuronide C0 (μg/mL) Cmax (μg/mL) Tmax, h, median (range) AUC0–12 (μg h/mL) AUC0–12/dose (ng h/mL per mg) Day 28 (n=9) Month 3 (n=4) Month 6 (n=8) 1080±311 32.3±4.2 7.1±16.8 25.5±25.4 2.4 (0.0–4.0) 44.4±25.1 78.4±28.7 810±180 27.3±6.6 2.4±1.5 21.5±22.3 6.0 (1.5–6.0) 67.1±51.5 181±149.4 900±385 25.6±7.9 4.6±5.8 12.9±7.3 6.0 (0.5–12.0) 41.7±15.3 102.7±45.4 92±78 183±77 3.5 (1.5–6.0) 1450±825 2643±1354 33±11 79±25 7.0 (6.0–12.0) 601±116 1548±482 38±19 71±37 5.0 (1.5–11.9) 522±264 1219±508 Values are given as mean ± standard deviation (SD) unless otherwise stated C0, Trough level; Cmax, peak concentration; Tmax, time to peak concentration; AUC0–12, concentration–time curve 400 exposure is likely to have been due to an unfamiliarity with C2 monitoring among the investigators. However, in this population, creatinine clearance was generally high at inclusion and, more importantly, remained stable throughout the study. In terms of pharmacokinetic data, the expected stabilization of MPA oral clearance (or dose-standardized AUC) over the first 3–12 months that has previously been described in adults and in MMF-treated pediatric patients was not obvious in our population. This was probably due to the small size of our patient cohort and the high interindividual variability that has previously been reported with MMF [22–24]. Indeed, there was almost a ten-fold variation in AUC0–12 and AUC0–12/dose values within this relatively small group of pediatric patients. The trough level of MPA measured in the morning was not a good surrogate marker of total exposure here. The evening pre-dose concentration (C12) was much better in this respect, as previously observed for MMF [23]. However, the small number of patients and fluctuating correlation coefficients at the different sampling points do allow us to draw a definitive conclusion on the feasibility of using C12 as a tool for EC-MPS monitoring and dose adjustment. One possibility is for the result is delayed or slower enterohepatic circulation of MPA at night-time. The MPA AUC levels were, unfortunately, not available for patients who discontinued EC-MPS due to side effects. Previous studies with MMF have shown that the AUC0–12 for total MPA (i.e. free MPA and MPA bound to plasma proteins) is predictive of efficacy in terms of preventing acute rejection [23, 25], but not predictive of toxicity. The GI adverse events could not be related to any exposure index, except in a small study where a tendency towards an association was observed [16], while infections and hematological toxicity appear to be related to free MPA AUC0–12 [23, 25]. The MPAG levels were, as expected, much higher than MPA levels. Again, there was a large variation in the ratio of MPAG/MPA AUC0–12, which ranged from 5.5 to 87.1 (mean 23±20). The stabilization of MPAG exposure was more apparent, with AUC0–12/dose decreasing progressively with increasing post-transplant time. A recent study in adult renal transplant patients found that glomerular filtration rate, ALT, serum albumin levels and mycophenolate dose explained 69% of the variability in total MPAG exposure [26]. Comparisons with the pharmacokinetics of MPA and MPAG in pediatric kidney transplants receiving MMF are necessarily limited by the small number of patients in the current population as well as in reports on MMF (n=9) [16]. Nevertheless, the published mean values for MPA Cmax and AUC0–12 in MMF-treated children (16.2 μg/mL and 57.0 μg h/mL, respectively) fell within the range of values observed here whereas, as expected, the Tmax values for MPA and Pediatr Nephrol (2009) 24:395–402 MPAG with EC-MPS were longer than those published with MMF in children (1–2 vs. 3.1 h, respectively) [16]. A mean MPAG AUC0–12 of 1515 μg h/mL was reported with MMF, which is higher than that observed in our population, but the MPAG Cmax on MMF (164 μg/mL) fell within the range of those recorded here at different time points. This was a pilot study, with a relatively small number of patients, and the results should be interpreted in that context. In addition to the high rate of study drug discontinuations, we are fully aware that the trial had no comparator arm. Although prospective trials in adult populations have shown therapeutic equivalence using EC-MPS and MMF [11, 12, 27, 28], and conversion from MMF to EC-MPS had been undertaken successfully in children [17, 18], the equivalence of EC-MPS and MMF in terms of efficacy and safety in pediatric renal transplant patients cannot be confirmed without a randomized study. No trial has been undertaken in pediatric patients using a regimen of MMF, CsA, steroids, and anti-IL-2 receptor antibody induction, so we are unable to even make an indirect cross-study comparison of the two formulations. In one trial of 100 patients receiving MMF, CsA, and steroids, in which 73/100 patients received antilymphocyte induction, the incidence of BPAR at 6 months post-transplant was 25% [6], but differences in year of transplant, CsA monitoring, and use of induction are likely to have accounted for this relatively high incidence versus the low rate of rejection in our study. A controlled trial of EC-MPS versus MMF with concomitant calcineurin inhibitor (CNI) therapy, steroids, and anti-IL-2 receptor antibody induction would be desirable, particularly if it were powered to detect a difference in the GI event rate. An improvement in GI tolerability with EC-MPS would also be of considerable interest, particularly in view of early evidence that MMFrelated GI symptoms may be more common in children than adults and that children are more likely to receive a dose modification or withdrawal if GI complications develop [29]. In conclusion, this pilot study suggests that a regimen of EC-MPS 450 mg/m2 b.i.d. with CsA, steroids and anti-IL-2 receptor antibody induction in pediatric renal transplant patients is associated with a low rate of acute rejection and results in good renal function. A larger, controlled trial is, however, required to confirm these findings and to provide comparative data versus MMF therapy. In such a study, adherence to suitable CNI exposure levels will be important to achieve an optimal balance of efficacy versus tolerability. References 1. Meier-Kriesche HU, Steffen BJ, Hochberg AM, Gordon RD, Liebman MN, Morris JA, Kaplan B (2003) Long-term use of Pediatr Nephrol (2009) 24:395–402 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. mycophenolate mofetil is associated with a reduction in the incidence and risk of late rejection. Am J Transplant 3:68–73 Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L, Barker C (1997) Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups. Transplantation 63:39–47 Ojo AO, Meier-Kriesche HU, Hanson JA, Leichtman AB, Cibrik D, Magee JC, Wolfe RA, Agodoa LY, Kaplan B (2000) Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation 69:2405–2409 Staskewitz A, Kirste G, Tonshoff B, Weber LT, Böswald M, Burghard R, Helmchen U, Brandis M, Zimmerhackl LB (2001) Mycophenolate mofetil in pediatric renal transplantation without induction therapy: results after 12 months of treatment. German Pediatric Renal Transplantation Study Group. Transplantation 71:638–644 Jungraithmayr T, Staskewitz A, Kirste G, Kirste G, Böswald M, Bulla M, Burghard R, Dippell J, Greiner C, Helmchen U, Klare B, Klaus G, Leichter HE, Mihatsch MJ, Michalk DV, Misselwitz J, Plank C, Querfeld U, Weber LT, Wiesel M, Tönshoff B, Zimmerhackl LB, German Pediatric Renal Transplantation Study Group (2003) Pediatric renal transplantation with mycophenolate mofetil-based immunosuppression without induction: results after three years. Transplantation 75:454–461 Hocker B, Weber LT, Bunchman T, Rashford M, Tonshoff B, Tricontinental MMF Suspension Study Group (2005) Mycophenolate mofetil suspension in pediatric renal transplantation: threeyear data from the tricontinental trial. Pediatr Transplant 9:504– 511 Cransberg K, Marlies Cornelissen EA, Davin JC, Van Hoeck KJ, Lilien MR, Stijnen T, Nauta J (2005) Improved outcome of pediatric kidney transplantation in the Netherlands – effect of the introduction of mycophenolate mofetil? Pediatr Transplant 9:104– 111 Ferraris JR, Ghezzi LF, Vallejo G, Piantanida JJ, Araujo JL, Sojo ET (2005) Improved long-term allograft function in pediatric renal transplantation with mycophenolate mofetil. Pediatr Transplant 9:178–182 Otukesh H, Sharifian M, Basiri A, Simfroosh N, Hoseini R, Sedigh N, Golnari P, Rezai M, Fereshtenejad M (2005) Mycophenolate mofetil in pediatric renal transplantation. Transplant Proc 37:3012– 3015 Arns W, Breuer S, Choudhury S, Taccard G, Lee J, Binder V, Roettele J, Schmouder R (2005) Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil. Clin Transplant 19:199–206 Salvadori M, Holzer H, De Mattos A, Sollinger H, Arns W, Oppenheimer F, Maca J, Hall M, The ERL B301 Study Groups (2004) Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 4:231–236 Budde K, Curtis J, Knoll G, Chan L, Neumayer HH, Seifu Y, Hall M, ERL B302 Study Group (2004) Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study. Am J Transplant 4:237–243 Chan L, Mulgaonkar S, Walker R, Arns W, Ambühl P, Schiavelli R (2006) Patient-reported gastrointestinal symptom burden and health-related quality of life following conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium. Transplantation 81:1290–1297 Behrend M (2001) Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management. Drug Saf 24:645–663 401 15. Ettenger R, Bartosh S, Choi L, Zhu W, Niederberger W, Campestrini J, Bastien MC, Schmouder R (2005) Pharmacokinetics of enteric-coated mycophenolate sodium in stable pediatric renal transplant recipients. Pediatr Transplant 9:780– 787 16. Jacqz-Aigrain E, Shaghaghi E, Baudoin V, Popon M, Zhang D, Maisin A, Loirat C (2000) Pharmacokinetics and tolerance of mycophenolate mofetil in renal transplant children. Pediatr Nephrol 14:95–99 17. Garcia CD, Bittencourt VB, Tumelero A, Malheiros D, Antonello JS, Garcia VD (2006) Enteric-coated mycophenolate sodium (ECMPS) in pediatric renal transplantation – single center experience. Transplantation 82[Suppl 3]:567 18. de Paula Meneses R, Kotsifas CH, Olandoski KP (2006) Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in children with stable renal transplant. Transplantation 82[Suppl 3]:510 19. World Medical Association (2000) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Available at: www.wma.net/e/policy/ 17-c_e.html 20. Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, Cavallo T, Croker BP, Demetris AJ, Drachenberg CB, Fogo AB, Furness P, Gaber LW, Gibson IW, Glotz D, Goldberg JC, Grande J, Halloran PF, Hansen HE, Hartley B, Hayry PJ, Hill CM, Hoffman EO, Hunsicker LG, Lindblad AS, Yamaguchi Y (1999) The Banff 97 working classification of renal allograft pathology. Kidney Int 55:713–723 21. Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A (1976) A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58:259–263 22. Weber LT, Lamersdorf T, Shipkova M, Niedmann PD, Wiesel M, Zimmerhackl LB, Staskewitz A, Schütz E, Mehls O, Oellerich M, Armstrong VW, Tönshoff B (1999) Area under the plasma concentration-time curve for total, but not for free, mycophenolic acid increases in the stable phase after renal transplantation: a longitudinal study in pediatric patients. German Study Group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients. Ther Drug Monit 21:498–506 23. Weber LT, Shipkova M, Armstrong VW, Wagner N, Schütz E, Mehls O, Zimmerhackl LB, Oellerich M, Tönshoff B (2002) The pharmacokinetic-pharmacodynamic 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 13:759–768 24. Ghio L, Ferraresso M, Viganò SM, Ginevri F, Perfumo F, Gianoglio B, Murer L, Zacchello G, Dello Strologo L, Cardillo M, Tirelli S, Valente U, Edefonti A (2005) Mycophenolate mofetil pharmacokinetic monitoring in pediatric kidney transplant recipients. Transplant Proc 37:856–858 25. Oellerich M, Shipkova M, Schütz E, Wieland E, Weber L, Tönshoff B, Armstrong VW (2000) Pharmacokinetic and metabolic investigations of mycophenolic acid in pediatric patients after renal transplantation: implications for therapeutic drug monitoring. German Study Group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients. Ther Drug Monit 22:20–26 26. Naesens M, de Loor H, Vanrenterghem Y, Kuypers DR (2007) The impact of renal allograft function on exposure and elimination of mycophenolic acid (MPA) and its metabolite MPA 7-Oglucuronide. Transplantation 84:362–373 27. Salvadori M, Holzer H, Civati G, Sollinger H, Lien B, Tomlanovich S, Bertoni E, Seifu Y, Marrast AC, ERL B301 Study Group on behalf of the ERL B301 Study Group (2006) Long-term adminis- 402 tration of enteric-coated mycophenolate sodium (EC-MPS; myfortic) is safe in kidney transplant patients. Clin Nephrol 66:112–119 28. Budde K, Knoll G, Curtis J, Chan L, Pohanka E, Gentil M, Seifu Y, Marrast AC, Neumayer HH, ERL B302 Study Group (2006) Long-term safety and efficacy after conversion of maintenance Pediatr Nephrol (2009) 24:395–402 renal transplant recipients from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS, myfortic). Clin Nephrol 66:103–111 29. Roberti I, Reisman L (1999) A comparative analysis of the use of mycophenolate mofetil in pediatric vs adult renal allograft recipients. Pediatr Transplant 3:231–235