Proc. West. Pharmacol. Soc. 54: 65-67 (2011)
Pre-Transplant Mycophenolate Mofetil Pharmacokinetics in Mexican Children
Villa, M.1, González, R.2, García-Roca, P.3, Hernández, A.M.3, Ortiz, L.3, Castañeda-Hernández, G.2
and Medeiros, M.3*
1Departamento de Nefrología, Hospital Infantil de México Federico Gómez; 2 Departamento de Farmacología, CINVESTAV-IPN,
3Laboratorio de Investigación en Nefrología, Hospital Infantil de México Federico Gómez, México D.F.
Received May 23, 2011; Accepted August 22, 2011
Mycophenolate mofetil is an immunosuppressive pro-drug frequently used to prevent renal graft rejection. It
is hydrolyzed by esterases to obtain the active drug mycophenolic acid (MPA). There is high inter-patient
variation in mycophenolic acid pharmacokinetics. Area under the concentration versus time curve (AUC) is
used for therapeutic drug monitoring and recommended levels are 30-60 g hr/L. The aim of this study was
to determine mycophenolic acid pharmacokinetics in children awaiting renal allograft in order to predict
mycophenolate mofetil dose requirements. Children with end-stage renal disease on the waiting list for renal
allograft transplantation were invited to participate in the study. A nine-point pharmacokinetic profile was
performed. All patients received a single dose (600 mg/m2, subcutaneously) of mycophenolate mofetil at time
zero. Mycophenolic acid was measured by HPLC. The AUC0-12h was estimated by the trapezoidal rule. Ten
children were included in the study. Mean age was 13.5 3.5 years. The median AUC0-12h was 20.3 g hr/L,
median Cmax = 0.7 g/mL. Two children (20%) had no detectable levels of mycophenolic acid after a single
mycophenolate mofetil dose, other two patients had AUC > 60 g hr/L. One patient had abdominal pain 1 hr
after the mycophenolate mofetil dose. Twenty percent of our patients had AUC0-12h higher than the
recommended value after a single mycophenolate mofetil dose, those patients should receive lower
mycophenolate mofetil dose since the beginning of the transplant to avoid adverse events, and another 20%
of patients had no detectable mycophenolic acid levels after a single mycophenolate mofetil dose. UGT1A9
gene polymorphisms remain to be studied in our patients, since they could explain the differences in
Mycophenolic acid (MPA) is a potent immune-
suppressant which inhibits inosine 5-monophosphate
dehydrogenase, an enzyme responsible for the de
novo pathway of guanosine nucleotide synthesis in B
and T lymphocytes, thus inhibiting cell proliferation
and suppressing antibody formation and cell-
mediated immune response. Since its approval by
FDA in 1995 it has become the most common
antiproliferative drug provided in renal trans-
plantation . Mycophenolate mofetil (MMF) is a
pro-drug, the 2,4-morpholinoethylester of MPA,
hydrolyzed by esterases in the gastrointestinal tract
blood and liver to obtain the active drug. Its
bioavailability is higher than 90%. Time to reach peak
concentration (tmax) is 1-2 hr [2,3]. A high inter-
patient variation of MPA pharmacokinetics has been
described, a second peak 6-12 hr after dosing can be
observed due to enterohepatic cycling. A non-linear
relationship between MMF dose and MPA exposure
has been described . Low serum albumin levels
lead to an increase in the MPA levels. The plasma
concentration versus time curve (AUC) is the
pharmacokinetic parameter of choice for therapeutic
drug monitoring because it predicts the risk of organ
rejection better than trough levels. To reduce the risk
of acute rejection the recommended AUC0-12h is 30-
60 g hr/L [5-7]. MPA is metabolized in the intestine
and liver to a stable, inactive phenolic glucuronide by
the uridine diphosphate-glucuronosyl transferase
enzymes (UGT) [8,9]. The main metabolite, the 7-
hydroxy-glucuronide of mycophenolic acid (MPAG)
generated by the isoenzyme UGT1A9, is inactive.
MPA side effects include
gastrointestinal complications that can lead to dose
reduction and low exposure levels with the risk of
acute rejection episodes or graft failure [10-12]. In a
previous study, we found that 50% of our renal
transplant children had overexposure to MPA, and
gastrointestinal adverse events were present in more
than 75% of the patients . The aim of the study
was to determine MPA pharmacokinetics in children
on the waiting list for renal allograft transplantation
in order to predict MMF dose requirements.
Material and Methods
The study was conducted according to recommendations
of the Declaration of Helsinki, it was approved by the
Hospital Internal Review Board and the Ethics Committee.
Parental written consent and assent of the patient was
obtained in all cases.
Children with end-stage renal disease on the waiting list
for renal allograft transplantation were invited to
Proc. West. Pharmacol. Soc. 54: 65-67 (2011)
participate in the study. An indwelling cannula was
inserted in a suitable forearm vein, 1 ml whole blood
samples were drawn at 0, 0.5, 1, 2, 3, 4, 6, 8 and 12 hr
following a single dose of MMF (CellCept®, Roche
Pharmaceuticals, Basel, Switzerland or Tevacept® TEVA
Pharmaceuticals, Mexico) provided as one or one and a
half 500 mg tablets to reach the nearest dose to 600
mg/m2 body surface area. The commercial brand provided
to the patient was chosen based on the approval of the
insurance provider for clinical
care after renal
MPA was measured by HPLC . Individual plasma-MPA
concentration-against time-curves were constructed. The
peak concentration (Cmax) and the time to reach the peak
concentration (tmax) were directly determined from these
plots. The area under the concentration-time curve (AUC0-
12h) was estimated by the trapezoidal rule. We used the
software program PhoenixWin Non Lin Version 6.0.
(Pharsight Corporation, St. Louis, MO, USA).
Statistical analysis. The data were analyzed using the
Graph Pad Prism software version 5.0a for Mac Os X
(GraphPad Software, San Diego, CA). Values are presented
as mean and standard deviation when normally
distributed and median with range of minimum and
maximum value for non-normally distributed data.
Results and Discussion
Ten children in the peritoneal dialysis program were
included, demographic data is depicted in Table I,
mean age was 13.6 3.5 years, four patients were
male; the cause of end stage renal disease was
unknown in 7 patients. Patients come to the hospital
usually when they need dialysis and in general with
small kidneys with no possibility to perform a renal
biopsy to determine the disease etiology. They
received a mean MMF single dose of 567 ± 24
mg/m2. Pharmacokinetic parameters are depicted in
Table II. The median AUC0-12h was 20.3 g hr/L (range
0-71), median Cmax 15.5 (range 0-34.9 g/mL),
median tmax 0.7 (range 0-2 g/mL). No statistically
significant difference was
commercial formulations (Cell Cept or Tevacept).
The concentration against time curve is depicted in
Figure 1, mean ± SE was plotted. Two children (20%)
had no detectable levels of MPA after a single MMF
dose, even though our study was not performed at
steady state, these patients maybe need an
increased MMF dose after renal transplant to achieve
therapeutic target levels. Adequate levels of
immunosuppressive drugs soon after transplant are
crucial to avoid acute rejection. Two other patients
(20%) had AUC0-12h > 60g h/mL, one of them
presented significant abdominal pain 1 hr after the
MMF dose. Such patients should receive a lower
MMF dose since the beginning of the transplant to
avoid adverse events.
Figure 1. MPA concentration against-time curve in ten end
stage renal disease children after a single MMF dose. Values
are mean ± SEM.
UGT1A9 gene polymorphisms remain to be studied in
our patients, since they could explain the differences
in bioavailability , also we intend to perform a
second pharmacokinetic study three months after
renal transplantation, to determine if the pre-
transplant pharmacokinetic profile predicts the
bioavailability after transplant.
Supported by Fondos Federales Protocol HIM/2011/013
Table I. Patient demographics
13.25 2.7 Age (years SD)
Gender (M/F) 4/6 2/4 2/2
Cause of end-stage
renal disease n(%)
7 (70 %)
2 (20 %)
Table II. Pharmacokinetics of MPA after a single dose of
MMF (CellCept® or Tevacept®) in 10 pre renal
transplant children. Values as median (min, max)
Parameter All (range)
0 (0, 4.1)
0 (0, 2.7)
C12 hr (μg/mL)
20 (0, 71) 20.4 (0, 66) 23 (0,71) 0.83
15.5 (0,34.9) 15.6 (0, 24) 12 (0, 34.9) 0.83
0.7 (0, 2) 0.7 (0,1) 0.7 (0, 2) 1.0
MPA: Mycophenolic acid, AUC: area under the time-concentration curve, p
value (CellCept vs. Tevacept) obtained by Mann Whitney test.
Proc. West. Pharmacol. Soc. 54: 65-67 (2011) Download full-text
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