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.
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