Pharmacokinetics of Mycophenolate Mofetil Metabolites in Older

Patients on the Seventh Day After Renal Transplantation

J. Sobiaka*, M. G»ydab,c, M. Maleca, and M. Chrzanowskaa
a
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan
, Poland; bDepartment of

District Hospital, Poznan
Transplantology and General Surgery, Poznan
, Poland; and cDepartment of Hepatobiliary and General
Surgery, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Bydgoszcz, Poland

ABSTRACT
Background. Currently, immunosuppression schemes are age-independent; however, physio-
logical changes may alter drugs’ pharmacokinetics in the older population. We compared myco-
phenolic acid (MPA) and its glucuronide metabolite (MPAG) pharmacokinetics among patients
aged <60 and >60 years on the seventh day after renal transplantation.
Methods. We included 7 and 10 renal transplant recipients, aged >60 and <60 years, respec-
tively, treated with mycophenolate mofetil. MPA and MPAG concentrations were determined
using the high-performance liquid chromatography method with ultraviolet detection (HPLC-
UV). Noncompartmental pharmacokinetic analysis was performed.
Results. In patients aged >60 years, mean MPA and MPAG concentrations before the next
dose and ratio of MPAG area under the concentration-time curve (AUC0-12) to MPA AUC0-12
were higher by 1.6-fold, 1.4-fold, and 1.9-fold, respectively. Other MPAG concentrations
appeared to be slightly higher (1.2- to 1.5-fold) in older patients. MPA apparent clearance was
similar in both groups, whereas volume of distribution at steady state was slightly higher (1.6-
fold) in patients aged >60 years. The variability of most MPA and some MPAG pharmacokinet-
ics was greater in patients aged >60 years. The MPA AUC0-12 target was achieved in 40% and
14% of patients aged <60 and >60 years, respectively. The highest MPAG concentrations and
AUC0-12 were observed for patients with the lowest glomerular filtration rate.
Conclusions. Higher variability of MPA and MPAG pharmacokinetic parameters, MPA
AUC0-12 above the reference range, higher values of MPAG pharmacokinetics in patients with
lower glomerular filtration rates, as well as lower proportion of patients achieving MPA targets
all indicate the need for therapeutic drug monitoring in renal transplant recipients aged >60 years
and to verify target MPA AUC0-12 for this population.

R ENAL transplantation is the treatment option for end-stage

renal failure irrespective of age; however, immunosuppression
schemes are similar for different age groups regardless of the physi-
ological differences in drug pharmacokinetics. Although the risk of
acute rejection is lower in the older population, this population is
more prone to immunosuppressants’ adverse effects [1]. Mycophe-
nolate mofetil (MMF) is considered a relatively safe immunosup-
pressant; however, therapeutic drug monitoring is recommended
for its active moiety, and mycophenolic acid (MPA) owing to its
variable pharmacokinetics. Numerous factors influence this variabil-
ity [2,3], but target pharmacokinetic values are recommended irre-
spectively of the patient’s age [3]. It remains unclear whether
immunosuppressant doses or targets should be adjusted in older
recipients [2]. In the case of calcineurin inhibitors (cyclosporine
[CsA] and tacrolimus [Tac]), some authors suggest that the doses
should be lower in older patients than in younger adults, whereas
This work was supported by Poznan University of Medical Sci-
ences (grant no. 502-14-33064130-10156).
*Address correspondence to Joanna Sobiak, PhD, Department
of Physical Pharmacy and Pharmacokinetics, Poznan University

ecickiego
of Medical Sciences, 6 Swi ˛ Street, Poznan
60-781,
Poland. Tel: +48 61 8546435; Fax: +48 61 8546430. E-mail:
jsobiak@ump.edu.pl

0041-1345/20 © 2021 The Authors. Published by Elsevier Inc. This is an open

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2212 Transplantation Proceedings, 53, 2212−2215 (2021)

METABOLITES AFTER RENAL TRANSPLANT
MMF doses should remain unchanged [3]. There are only a few
studies concerning MPA pharmacokinetics in the older population,
with contradictory results [4-6]. We therefore compared MPA and
its glucuronide metabolite (MPAG) pharmacokinetics in renal
transplant recipients aged <60 and >60 years on the seventh day
after the surgery.
MATERIALS AND METHODS
We included 7 patients >60 years (mean 65 § 2 years; 5/1, women/
men; 5/2, Tac/CsA) and 10 patients <60 years (mean 40 § 11 years; 7/
3, women/men; 5/5, Tac/CsA) on the seventh day after renal transplan-
tation, receiving oral MMF (Cellcept, Roche, Grenzach-Wyhlen, Ger-
many) at a dose of 1000 mg twice a day. Blood samples were collected
before the morning dose of MMF (Ctrough), and 40 minutes (C0.67),
1 hour (C1), 2 hours (C2), 3 hours (C3), 4 hours (C4), 6 hours (C6),
8 hours (C8), and 10 hours (C10) after. MPA and MPAG plasma con-
centrations were determined using the validated high-performance liq-
uid chromatography method [7,8]. Pharmacokinetic parameters were
calculated based on the noncompartmental technique with the Phoenix
WinNonlin version 8.0 software (Certara, Princeton, NJ, United States).
MPA concentration 12 hours (C12) after drug administration and Ctrough
were assumed to be equal owing to twice a day regimen and the steady
state in all patients [9]. Plasma maximum concentration (Cmax), time to
reach Cmax (tmax), area under the concentration vs time curve (AUC0-
12), elimination rate constant (kel), and biological half-life (t0.5) were
calculated for MPA and MPAG, whereas clearance (Cl/F), steady-state
volume of distribution (Vd,ss/F), second MPA peak concentration
(Cmax2), and time to reach Cmax2 (tmax2) were determined for MPA
only. MPAG AUC0-12/MPA AUC0-12 ratio was calculated as well.
2213
Target MPA Ctrough, AUC0-12 of 1 to 3.5 mg/mL and 30 to 60 mg
h/mL
for CsA coadministration and 1.9 to 4 mg/mL and 35 to 60 mg
h/mL
for Tac coadministration were accepted [10]. The study was approved
by the Bioethical Committee at Poznan University of Medical Sciences
and is in accordance with the Declaration of Helsinki of 1975. Informed
consent was obtained from the patients before initiating the study.
RESULTS
The older patients were, on average, 25 years older than the
younger patients. For patients aged >60 years, mean MPA and
MPAG Ctrough were higher by 1.6-fold and 1.4-fold, respectively.
Other MPAG concentrations were slightly higher (1.2- to 1.5-
fold). MPAG AUC0-12/MPA AUC0-12 ratio was almost 2-fold
higher and more variable in patients aged >60 years (Fig 1).
MPA Cl/F was similar in both groups, whereas Vd,ss/F was
slightly higher (1.6-fold) in patients aged >60 years. The variabil-
ity of most MPA and MPAG pharmacokinetic parameters was
greater in patients >60 years (Table 1). For patients aged
<60 years and >60 years, MPA Ctrough within the recommended
range was achieved in 50% and 43%, respectively, and MPA
AUC0-12 was achieved in 40% and 14% of patients, respectively.
Only in patients aged >60 years did Ctrough and AUC0-12 exceed
the recommended range. Irrespective of age, MPA Ctrough and
Cmax2 were 2.3-fold and 4-fold higher when Tac was coadminis-
tered, whereas MPA Cl/F was 1.9-fold higher for CsA coadminis-
tration. For 2 patients (aged 29 and 64 years) with glomerular
filtration rate <10 mL/min, high MPAG concentrations
Fig 1. MPA (A) and MPAG (B) concentration-time curves for
patients aged <60 years and >60 years. MMF, mycophenolate
mofetil; MPA, mycophenolic acid; MPAG, mycophenolic acid
glucuronide.
2214 SOBIAK, G»YDA, MALEC ET AL

Table 1. MPA and MPAG pharmacokinetics

<60 Years (n = 10) >60 Years (n = 7)

Parameter Mean § SD Range CV% Mean § SD Range CV%

MPA Ctrough [mg/mL] 1.32 § 0.68 0.33-2.52 51 2.06 § 1.88 0.41-5.51 91

<target n = 3/5 (CsA), n = 2/5 (Tac) n = 1/2 (CsA), n = 2/5 (Tac)
>target n = 0/5 (CsA), n = 0/5 (Tac) n = 0/2 (CsA), n = 1/5 (Tac)
Cmax [mg/mL] 6.81 § 2.95 3.01-11.03 43 7.64 § 3.66 2.03-12.50 48
tmax [h] 2§1 0.67-4 70 1§0 0.67-2 38
Cmax2 [mg/mL] 3.15 § 2.19* 0.63-6.60 70 4.69 § 3.27y 1.31-8.74 70
tmax2 [h] 7 § 2* 6-10 20 7 § 2y 4-10 34
ke [L/h] 0.170 § 0.059 0.070-0.250 35 0.123 § 0.087 0.040-0.310 70
t0.5 [h] 4.9 § 2.8 2.8-10.5 57 7.6 § 4.1 2.3-15.7 54
AUC0-12 [mg
h/mL] 30.99 § 13.21 15.26-54.12 43 36.70 § 24.03 11.19-74.69 65
<target n = 3/5 (CsA), n = 3/5 (Tac) n = 2/2 (CsA), n = 2/5 (Tac)
>target n = 0/5 (CsA), n = 0/5 (Tac) n = 0/2 (CsA), n = 2/5 (Tac)
Cl/F [L/h] 27.6 § 10.6 13.7-48.4 38 29.5 § 19.4 9.9-66.1 66
Vd,ss/F [L] 180 § 86 80-378 48 294 § 173 57-557 59
MPAG Ctrough [mg/mL] 108.1 § 41.4 70.9-208.7 38 154.2 § 146.0 49.3-464.1 95
Cmax [mg/mL] 161.7 § 60.0 98.4-315.1 37 202.8 § 161.9 73.0-546.7 80
tmax [h] 5§3 0.67-10 63 4§2 2-6 43
ke [L/h] 0.047 § 0.039 0.010-0.140 82 0.036 § 0.016 0.020-0.060 45
t0.5 [h] 28.6 § 28.4 4.9-101.4 100 24.1 § 11.4 10.9-38.8 47
AUC0-12 [mg
h/mL] 1549 § 618 968-3153 40 2052 § 1760 618-5769 86
MPAG AUC0-12/MPA AUC0-12 ratio 58 § 28 18-114 48 109 § 181 23-516 166
AUC0-12, area under the concentration-time curve from 0 to 12 hours; Cl/F, apparent clearance; Cmax, maximum concentration; Cmax2, second maximum concentra-
tion; CsA, cyclosporine; Ctrough, concentration before the next dose; CV, coefficient of variation; ke, elimination rate constant; MPA, mycophenolic acid; MPAG, mycophe-
nolic acid glucuronide; SD, standard deviation; Tac, tacrolimus; tmax, time to reach maximum concentration; tmax2, time to reach the second maximum concentration; t0.5,
biological half-life; Vd,ss/F, volume of distribution at steady state.
* MPA Cmax2 and tmax2 was noticeable in 7 of 10 patients <60 years
y
MPA Cmax2 and tmax2 was noticeable in 5 of 7 patients >60 years

(>200 mg/mL) and AUC0-12 (>3000 mg h/mL) were observed.
MPA Ctrough was within the target value only in the younger
patient. Both patients had MPA AUC0-12 <30 mg h/mL.
DISCUSSION
With the aging population, more studies focusing on numerous
aspects of health care are needed to provide patients with safe
and effective treatments [11]. There are few studies to date
describing the effects of aging on MPA metabolites, and those
that exist have contradictory results [2,4,5]. We compared MPA
and MPAG pharmacokinetics in patients aged >60 and <60 years.
Data from the literature suggest either a lack of age influence on
MMF metabolite pharmacokinetics or lower MPA pharmacoki-
netics in the older population [4,5], despite similar MPA Cmax
between older and younger patients [6]. Our results suggested
increased and more variable MPA and MPAG pharmacokinetics
in older patients, with the exception of MPA Cl/F. Generally, in
the early posttransplant period, mean MPA AUC0-12 is about
30% lower than in the late posttransplant period (3-6 months
afterward) [12]; however, greater variability of pharmacokinetics
in patients >60 caused MPA AUC to be below, within, and also
above the recommended range, whereas in younger patients the
upper value was not exceeded. This observation, along with a
low percentage of MPA AUC0-12 within the target in older
patients and no early rejection observed, may suggest the need to
verify MPA AUC0-12 target values for the older population in a
larger group. Lower MPA AUC0-12 may be desirable in the older
population because lower-maintenance immunosuppressant tar-
gets in older recipients may decrease patient susceptibility to drug
adverse effects. Some authors have observed similar effectiveness
of lower and standard MMF doses in renal transplant recipients
aged >60 years; however, they did not determine MPA concen-
trations [2,13].
The type of calcineurin inhibitor coadministered affects MPA
pharmacokinetics [14]; however, because of the small number of
patients, we did not make any observations. In a few CsA
cotreated and also Tac cotreated patients, enterohepatic recircula-
tion did not occur. Generally, MPA pharmacokinetic parameters
were higher in patients receiving Tac, as in the literature [3].
We observed concomitantly higher values of MPAG pharma-
cokinetics and lower glomerular filtration rate, as in the litera-
ture [14,15]. These relations are caused by the accumulation of
uremic toxins and the competition with albumin-binding sites
[14]. In patients treated with another MPA formulation, enteric-
coated mycophenolate sodium, we also observed higher MPAG
pharmacokinetics [16]. Monitoring of MPAG along with MPA
is considered a great improvement in therapy, because MPAG
represents a big part of MPA levels and may be related to the
increase of adverse effects; however, further studies on MPAG
AUC are needed [17].
CONCLUSIONS
Higher variability of MPA and MPAG pharmacokinetic param-
eters, MPA AUC0-12 above the reference range, higher values
METABOLITES AFTER RENAL TRANSPLANT
of MPAG pharmacokinetics in patients with lower glomerular
filtration rates, as well as lower proportion of patients achieving
MPA targets all indicate a need for MPA therapeutic drug moni-
toring in renal transplant recipients aged >60 years. Further
studies with a greater number of subjects are required to verify
target MPA AUC0-12 for these patients.
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