Copyright ª Blackwell Munksgaard 2006

Clin Transplant 2006: 20 (Suppl. 17): 80–84

Review of the clinical experience with a

modified release form of tacrolimus
[FK506E (MR4)] in transplantation
Wente MN, Sauer P, Mehrabi A, Weitz J, Büchler MW, Schmidt J, Moritz N. Wentea, Peter Sauerb,
Schemmer P. Review of the clinical experience with a modified release form Arianeb Mehrabia, Jürgen Weitza,
of tacrolimus [FK506E (MR4)] in transplantation. Markus W. Büchlera, Jan Schmidta
Clin Transplant 2006: 20 (Suppl. 17): 80–84. ª Blackwell Munksgaard, 2006 and Peter Schemmera
Departments of aGeneral Surgery and bInternal
Abstract: Non-compliance in solid transplantation recipients is a major
Medicine, Ruprecht-Karls-University,
factor in acute graft rejection, which influences patient survival. Nowadays,
Heidelberg, Heidelberg, Germany
tacrolimus is one of the most widely used immunosuppressant agents to-
gether with cyclosporine following kidney and liver transplantation with a
standardized twice-daily dosing regimen. To improve the patientsÕ compli- Key words: compliance – immunosuppression –
ance to the prescribed immunosuppressive therapy, FK506E (MR4), a kidney transplantation – liver transplantation –
modified release (MR) oral dosage form of tacrolimus has been developed tacrolimus
for a once-daily dosing regimen. This report reviews the most recent results
of clinical trials with MR tacrolimus after kidney and liver transplantation. Corresponding author: Peter Schemmer MD,
Department of General Surgery, Ruprecht-Karls-
University, Im Neuenheimer Feld 110, D-69120
Heidelberg, Germany.
Tel.: +49 6221 56 36500;
fax: +49 6221 56 5450;
e-mail: peter.schemmer@med.uni-heidelberg.de

Since the discovery and isolation of tacrolimus
from Streptomyces tsukubaensis in 1984, consecu-
tive determination of the chemical structure and
in vitro experiments revealed highly potent immu-
nosuppressive properties (1). Today, tacrolimus is
an established immunosuppressive agent marketed
worldwide under the tradename Prograf (Astellas
Pharma GmbH, Munich, Germany) for the pro-
phylaxis and treatment of allograft rejection pri-
marily in liver and kidney transplantation. In
clinical practice, a daily oral dose of tacrolimus is
administered as a twice-daily dosing regimen. The
optimal therapeutic range of tacrolimus is 10–
20 ng/mL in the early post-transplant period; in
higher concentrations, adverse effects might occur
more frequently, whereas in lower concentrations,
an increased risk of acute rejection has been
described (2). Following innovative results from
initial randomized controlled trials for primary
immunosuppressive therapy and rescue therapy in
liver transplant recipients, tacrolimus led to less
frequent acute rejection rates compared with
cyclosporine and with the potential reverse of
refractory rejection. Tacrolimus was hence
approved by the FDA for use in liver transplan-
tation in 1994; the approval for kidney transplan-
tation was given in 1997 (3–5). Nowadays, in the
US tacrolimus is used in 89% and 67% of de novo
liver and kidney transplant recipients respectively,
making it the most widely used immunosuppressive
drug in solid organ transplantation (1, 6).
After transplantation, non-compliance of the
recipient to the use of immunosuppressive drugs
impairs not only the quality of life, but also
significantly reduces the survival of the patient
(7–9). Poor compliance and non-adherence are
responsible for up to a quarter of all deaths in
initially recovered patients and are the major risk
factors for graft rejection (10, 11). Compliance of
patients to the immunosuppressive drugs depends
on the dosing regimen, which is reflected by the
number of drugs to be taken (12). Therefore, a new

80

modified release (MR) oral dosage form of tacrol-
imus, FK506E (MR4), has been developed at
Astellas Pharma (formerly Fujisawa), which en-
ables a once-daily dosing regimen with an im-
proved pharmacokinetic profile compared with
that of the current tacrolimus formulation. This
might improve patient compliance, consecutively
improve graft function and further result in the
reduction of mortality rates (13, 14). This is a brief
overview of the published results of clinical trials
with MR tacrolimus after kidney and liver trans-
plantation.
MR tacrolimus in kidney transplantation
Conversion from standard tacrolimus to MR tacrolimus
Steinberg et al. evaluated the safety and efficacy of
converting from standard twice-daily tacrolimus to
MR tacrolimus once-daily in 70 stable kidney
transplanted patients in a one-yr follow-up study.
Following an initial 35-d period of pharmacoki-
netic evaluation, 67 patients entered the one-yr
monitoring period. In the follow-up period, no
significant changes in laboratory values were
examined; the baseline value for serum creatinine
was 1.37 mg/dL (0.7–3.6), whereas at one yr the
value for serum creatinine was 1.51 mg/dL (0.7–
3.1). After one yr, the use of lipid lowering and
antihypertensive drugs was reduced by 7% and
8%, respectively; no changes in the use of antidi-
abetic drugs could be evaluated. Two patients
developed a biopsy-proven acute rejection; three
patients aborted the therapy with MR tacrolimus,
one patient was lost to follow-up. Overall, the
authors concluded that one yr after conversion to
MR tacrolimus, their results confirmed the safety
and efficacy of MR tacrolimus in stable kidney
transplanted patients (15). Results of this study
have also been reported in abstract form before
(16, 17). Recently, a more detailed report on the
pharmacokinetic evaluation in this study popula-
tion has been published (18).
MR tacrolimus (de novo) in kidney transplant recipients
In a randomized, open-label, multicentre trial in
kidney transplant recipients with de novo MR
tacrolimus, Undre et al. compared the use of
standard tacrolimus vs. MR tacrolimus for a
period of six wk. The initial tacrolimus dosage
was 0.20 mg/kg body weight with target whole
blood trough levels of 10–20 ng/mL for days 1–14
and 5–15 ng/mL for days 15 until end of study
after six wk. Sixty-six patients were included in the
study, being randomized to the standard tacroli-
FK506E (MR4) in transplantation
mus group (n ¼ 32) and MR tacrolimus group
(n ¼ 34). The authors found a clear correlation
between AUC and Cmin for MR tacrolimus and
standard tacrolimus (r ¼ 0.9). In addition, efficacy
measurements determined comparable rates of
biopsy-proven acute rejection in both treatment
arms with 13% and 15% for MR tacrolimus and
standard tacrolimus, respectively. In addition, a
better inter-subject variability was described lead-
ing to a potentially improved patient management
(19).
MR tacrolimus in liver transplantation
Conversion from standard tacrolimus to MR tacrolimus
Alloway et al. reported a conversion study that is
similar to the above mentioned study after kidney
transplantation by Steinberg et al. In this study, 70
stable liver transplanted patients who changed
from standard tacrolimus to MR tacrolimus were
evaluated. After an initial pharmacokinetic period
of 56 d, 65 patients entered the one-yr follow-up
period. No significant changes in tested laboratory
parameters were observed during both periods of
the study; in addition, no changes in the concom-
itant medication for diabetes mellitus, hyperlipide-
mia or hypertension were discovered. In three
patients, a biopsy-proven acute rejection was
discovered; furthermore, seven patients discontin-
ued MR tacrolimus because of adverse effects and
five patients withdrew consent or stopped taking
the study medication. Based on the study results,
the authors concluded that MR tacrolimus is safe
and efficacious after conversion from standard
tacrolimus to MR tacrolimus in stable liver trans-
planted patients (20–22). Recently, a more detailed
report on pharmacokinetics has been published for
this study population (23).
Conversion from standard tacrolimus to MR tacrolimus in
pediatric liver transplant recipients
Preliminary pharmacokinetic results have been
presented by Heffron et al. in a group of liver
transplant recipients £ 12 yr of age and at least six
months after transplantation prior to enrolment in
this open-label multicentre study. Patients received
stable doses of standard tacrolimus at least two wk
before inclusion and had stable renal function. To
evaluate pharmacokinetic profiles, the patients
were first treated with standard tacrolimus on days
1–7 after which a milligram-to-milligram daily dose
conversion to MR tacrolimus was undertaken. The
AUC0)24 ratio of MR tacrolimus and standard
tacrolimus was 100.9% [90% CI: 90.8; 112.1] at
81
82
Wente et al.

Table 1. Literature on MR tacrolimus in transplantation

Author Year Type of study Number of patients Results Treatment

MR tacrolimus in kidney transplantation

Steinberg et al. (15) 2005 (abstract) Open-label trial N ¼ 70, stable kidney Reduction of antihypertensives and lipid-lowering drugs Conversion from standard to
Alloway et al. (16) 2004 (abstract) transplanted No significant changes in laboratory values MR tacrolimus
Alloway et al. (17) 2004 (abstract) Conclusion: conversion safe and efficacious
Alloway et al. (18) 2005
Undre et al. (19) 2005 (abstract) RCT N ¼ 66, N ¼ 32 standard, Comparable rates of acute rejection with 15% in Comparison standard vs. MR
N ¼ 34 MR tacrolimus de novo standard group and 13% in MR tacrolimus group tacrolimus (de novo)
kidney transplant recipients Better inter-subject variability for MR tacrolimus
six wk evaluation Conclusion: potentially improved patient
management
MR tacrolimus in liver transplantation
Alloway et al. (20) 2005 (abstract) Open-label trial N ¼ 70, stable liver transplanted No changes in concomitant medication Conversion from standard
Florman et al. (21) 2004 (abstract) Three acute rejections to MR tacrolimus
Florman et al. (22) 2004 (abstract) Conclusion: conversion safe and efficacious
Florman et al. (23) 2005
Heffron et al. (24) 2005 (abstract) Open-label trial N ¼ 18, £ 12 yr of age stable liver Preliminary pharmacokinetic data comparable Conversion from standard to MR
transplanted tacrolimus in pediatric patients
Undre et al. (25) 2005 (abstract) RCT N ¼ 77, N ¼ 32 standard, Comparable data of efficacy and safety Comparison standard vs. MR
N ¼ 45 MR tacrolimus de novo Overall, 27% acute rejection rate tacrolimus (de novo)
liver transplant recipients Better inter-subject variability for MR tacrolimus
six wk evaluation Conclusion: potentially improved patient management

RCT; randomized-controlled trial.


steady state. The Cmin ratio of MR tacrolimus and
standard tacrolimus was 91.8% [90% CI: 82.6;
102.2] with a high correlation of Cmin and AUC0)24
for standard tacrolimus (day 7: r ¼ 0.94) and MR
tacrolimus (day 14: r ¼ 0.90). Long-term safety
and efficacy of MR tacrolimus after conversion
from standard tacrolimus in stable pediatric liver
transplant recipients are currently under evaluation
(24).
MR tacrolimus (de novo) in liver transplant recipients
Undre et al. performed a randomized, open-label,
multi-centre trial in liver transplant recipients
comparing standard tacrolimus and MR tacroli-
mus for a period of six wk. This study is similar to
their kidney transplantation study with de novo
MR tacrolimus (19). Overall, 77 patients were
included with randomization to MR tacrolimus
(n ¼ 32) and standard twice-daily tacrolimus (n ¼
45). The starting dose in both groups was 0.10–
0.15 mg/kg body weight/d with target blood
trough levels of 10–20 ng/mL.
Pharmacokinetic analyses revealed a clear cor-
relation between AUC and Cmin (r ¼ 0.9) for
standard and MR tacrolimus with similar efficacy
data of a biopsy-proven acute rejection rate of
27% and comparable safety results. Again, the
inter-subject variability was lower for the MR
tacrolimus leading to a putatively improved patient
management (25).
Summary
According to the published data (Table 1), a once-
daily regimen with MR tacrolimus shows in terms
of safety and efficacy comparable data with a
standard twice-daily regimen with standard tacr-
olimus. Two studies with a one-yr follow-up period
revealed stable graft function following conversion
from standard tacrolimus to MR tacrolimus in
both stable kidney and liver transplant recipients.
Furthermore, the conversion of standard to MR
tacrolimus to MR tacrolimus in stable pediatric
liver transplant recipients revealed similar pharma-
cokinetic results.
Two randomized controlled trials have been
published in abstract form, analyzing the de novo
use of MR tacrolimus compared with standard
tacrolimus in both kidney and liver transplant
recipients. These trials revealed comparable results
for efficacy and safety with an improved inter-
subject variability, leading to the fulfilment of the
preliminary goal to enhance patient compliance.
Based on these preliminary results, the extended
release formulation of tacrolimus with its addi-
FK506E (MR4) in transplantation
tional benefit of a once daily application seems to
be comparable with standard tacrolimus with
similar exposure (AUC0)24) and correlation be-
tween AUC and Cmax. More detailed results and
larger randomized controlled trials are mandatory
to finally prove this hypothesis.
Acknowledgement
We thank Genevieve Dei-Anane for native speaker review
of the manuscript.
References
1. Busuttil RW, Lake JR. Role of tacrolimus in the evo-
lution of liver transplantation. Transplantation 2004: 77:
S44.
2. Undre NA, Stevenson P, Schafer A. Pharmacokinetics
of tacrolimus: clinically relevant aspects. Transplant Proc
1999: 31: 21S.
3. European FK506 Multicenter Liver Study Group. Rand-
omised trial comparing tacrolimus (FK506) and cyclo-
sporin in prevention of liver allograft rejection. Lancet
1994: 344: 423.
4. Klintmalm GB, Goldstein R, Gonwa TH, US Multi-
center FK506 Liver Study Group. Use of prograf (FK506)
as rescue therapy for refractory rejection after liver trans-
plantation. Transplant Proc 1993: 25: 679.
5. US Multicenter FK506 Liver Study Group. A comparison
of tacrolimus (FK506) and cyclosporine for immunosup-
pression in liver transplantation. N Engl J Med 1994: 331:
1110.
6. First MR, Fitzsimmons W. Modified release tacrolimus.
Yonsei Med J 2004: 45: 1127.
7. Didlake RH, Dreyfus K, Kerman RH, Van Buren CT,
Kahan BD. Patient noncompliance: a major cause of late
graft failure in cyclosporine-treated renal transplants.
Transplant Proc 1998: 20: 63.
8. Hilbrands LB, Hoitsman AJ, Koene RA. Medication
compliance after renal transplantation. Transplantation
1995: 60: 914.
9. Sketris I, Waite N, Grobler K, West M, Gerus S.
Factors affecting compliance with cyclosporine in adult
renal transplant patients. Transplant Proc 1994: 26: 2538.
10. Bunzel B, Laederach-Hofmann K. Solid organ trans-
plantation – are there predictors for posttransplant non-
compliance? A literature overview. Transplantation 2000:
70: 711.
11. Butler JA, Roderick P, Mullee M, Mason JC, Pev-
eler RC. Frequency and impact of nonadherence to im-
munosuppressants after transplantation: a systematic
review. Transplantation 2005: 77: 769.
12. Regazzi MB, Alessiani M, Rinaldi M. New strategies in
immunosuppression. Transplant Proc 2005: 37: 2675.
13. First MR, Fitzsimmons W. New drugs to improve
transplant outcomes. Transplantation 2004: 77: S88.
14. Schweizer RT, Rovelli M, Palmeri D, Vossler E,
Hull D, Bartus S. Noncompliance in organ transplant
recipients. Transplantation 1990: 49: 374.
15. Steinberg S, Tacrolimus Modified Release Stable Kidney
Conversion Study Group. A one year follow-up study of
stable kidney transplant recipients converted from twice
daily prograf to once daily modified release tacrolimus.
Am J Transplant 2005: 5: 193. (abstract).
83
Wente et al.
16. Alloway R, Tacrolimus Modified Release Kidney Con-
version Study Group. Conversion of stable kidney trans-
plant recipients from a twice daily prograf based regimen
to a once daily modified release tacrolimus based regimen.
Transplantation 2004: 78: 142. (abstract).
17. Alloway R, Tacrolimus Modified Release Kidney Con-
version Study Group. Conversion of stable kidney trans-
plant recipients from a twice daily prograf based regimen
to a once daily modified release tacrolimus based regimen.
Am J Transplant 2004: 4: 230 (abstract).
18. Alloway R, Steinberg S, Khalil K, Gourishankar S,
Miller J, Norman D et al. Conversion of stable kidney
transplant recipients from a twice daily prograf based
regimen to a once daily modified release tacrolimus based
regimen. Transplant Proc 2005: 37: 867.
19. Undre A, Tacrolimus Modified Release Kidney Study
Group. Use of a once daily modified release tacrolimus
regimen in de novo kidney transplant recipients. Am J
Transplant 2005: 5: 190 (abstract).
20. Alloway R, Tacrolimus Modified Release Stable Liver
Conversion Study Group. A one year follow-up study of
stable liver transplant recipients converted from twice daily
prograf to once daily modified release tacrolimus. Am J
Transplant 2005: 5: 393 (abstract).
84
21. Florman S, Tacrolimus Modified Release Liver Conver-
sion Study Group. Conversion of stable liver transplant
recipients from a twice daily prograf based regimen to a
once daily modified release tacrolimus based regimen.
Transplantation 2004: 78: 119 (abstract).
22. Florman S, Tacrolimus Modified Release Liver Conver-
sion Study Group. Conversion of stable liver transplant
recipients from a twice daily prograf based regimen to a
once daily modified release tacrolimus based regimen. Am
J Transplant 2004: 4: 268 (abstract).
23. Florman S, Alloway R, Kalayoglu M, Lake K, Bak
T, Klein A et al. Conversion of stable liver transplant
recipients from a twice daily prograf based regimen to a
once daily modified release tacrolimus based regimen.
Transplant Proc 2005: 37: 1211.
24. Heffron TG, Tacrolimus Modified Release Liver Con-
version Study Group. Conversion of stable pediatric liver
transplant recipients from twice daily prograf to once daily
modified release tacrolimus. Am J Transplant 2005: 5: 511
(abstract).
25. Undre A, Tacrolimus Modified Release Liver Study
Group. Use of a once daily modified release tacrolimus
regimen in de novo liver transplant recipients. Am J
Transplant 2005: 5: 374 (abstract).