Transplant Immunology 28 (2013) 198–202

Contents lists available at SciVerse ScienceDirect

Transplant Immunology
journal homepage: www.elsevier.com/locate/trim

Tacrolimus therapeutic drug monitoring in Tunisian renal

transplant recipients: Effect of post-transplantation period☆
N. Ben Fredj a,⁎, A. Chaabane a, Z. Chadly a, M. Hammouda b, S. Aloui b, N.A. Boughattas a,
H. Skhiri b, K. Aouam a
a
Service de Pharmacologie, Faculté de Médecine, Monastir, Tunisia
b
Service de Nephrologie, EPS Monastir, Tunisia

a r t i c l e i n f o a b s t r a c t

Article history: Background: Most previous studies having focused on therapeutic drug monitoring of tacrolimus in renal
Received 29 December 2012 transplant recipients have assessed the clinical response of patients. The aim of this study is to investigate
Received in revised form 10 April 2013 the influence of post-transplant delay on tacrolimus dose, trough levels (C0) and dose/C0 ratio in a Tunisian
Accepted 10 April 2013 renal transplant population.
Patients and methods: A retrospective study including 110 renal transplant patients has been performed. Ta-
Keywords:
crolimus trough concentrations were adjusted according to the target range proposed by the European con-
Therapeutic drug monitoring
Tacrolimus
sensus conference on tacrolimus optimization. Samples for determination of tacrolimus blood level were
Kidney transplantation subdivided according to the post-transplantation period into three groups.
Post-transplantation time Results: The initial dose required was 0.17 ± 0.05 mg/kg/day during the first 3 months after transplantation.
A reduction of 36 and 65% of tacrolimus initial dose during the second (3–12 months) and third period after
transplantation (>12 months), respectively, was required to maintain the concentration level within thera-
peutic range. These results were different from those found in other studies performed in different popula-
tions. We hypothesize that these differences in dosing requirement may be due to an interethnic
polymorphism in the expression of enzymes involved in tacrolimus metabolism.
Conclusion: These results could provide a simple therapeutic strategy to optimize tacrolimus prescription
after renal transplantation in Tunisian population.
© 2013 Elsevier B.V. All rights reserved.

1. Introduction transplantation (3 months–12 months), and from 5 ng/ml to 10 g/ml

Tacrolimus is a potent immunosuppressant drug that is well
established for primary immunosuppression in kidney transplantation.
It was introduced in the late 1980s as an alternative to cyclosporine-A
for the prevention of graft rejection following solid organ transplanta-
tion [1]. Based on its high inter and intra-individual pharmacokinetic
variability, therapeutic drug monitoring is essential to avoid graft rejec-
tion and drug toxicity.
In order to obtain an optimal efficacy and a minimal toxicity, the
European experts on tacrolimus have recently proposed new target
ranges of trough concentration based on both drug combination and
post-transplantation delay. This consensus conference on Tacrolimus
optimization concluded that tacrolimus whole blood concentrations
should range from 10 to 15 ng/ml during the first 3 months after trans-
plantation, and then from 8 to 12 ng/ml during the second period after
☆ Conflict of interest: None.
⁎ Corresponding author at: Laboratoire de Pharmacologie, Faculté de Médecine de
Monastir, Rue Avicenne, 5019 Monastir, Tunisia. Tel.: +216 22 65 78 08.
E-mail address: benfredj.nadia@gmail.com (N. Ben Fredj).
thereafter [2].
Only few studies have assessed the corresponding recommended
tacrolimus dose corresponding to therapeutic concentrations ranges
according to time post-transplantation [3–5] and, to our knowledge,
there have been no reports of such studies performed on Tunisian
kidney transplant recipients.
The aim of this study is to investigate the influence of post-
transplant delay on tacrolimus dose, trough levels (C0) and dose/C0
ratio in a Tunisian renal transplant population.
2. Patients and methods
We performed a retrospective study including one hundred and ten
Tunisian patients undergoing renal transplantation. Their tacrolimus
blood samples were obtained between March 2009 and December
2011. All patients were treated with a combined immunosuppressive
therapy based on tacrolimus, mycophenolic acid and prednisone. The
initial tacrolimus dose (Prograf*, Hikma) was 0.15 mg/kg per day ad-
ministered in two divided doses, and started the same day of renal
transplantation. Subsequent tacrolimus doses were adjusted to

0966-3274/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.trim.2013.04.003
 N. Ben Fredj et al. / Transplant Immunology 28 (2013) 198–202 199

Table 1 Statistical analyses were performed using the platform-

Patients' characteristics. independent basic-statistics GUI for R (Rcmdr R package) software
Group 1 Group 2 Group 3 version 1.9–4. A univariate analysis using ANOVA test was carried
(n = 141) (n = 170) (n = 146) out to compare continuous parameters in different groups. A Chi
Age (year) 31.6 ± 11.9 26 ± 9.3 33.0 ± 8.0 square test was performed to compare gender in three groups.
Gender (M/F) 41/18 18/8 16/9 Then, we have performed a multivariate analysis using a backward
Weight (kg) 58.2 ± 13.8 61.5 ± 13.3 65.9 ± 11.1 stepwise multiple regression analysis (Generalized Linear Model,
Tac doses (mg/kg/day) 0.17 ± 0.06 0.11 ± 0.06 0.06 ± 0.04
Rcmdr R package) in order to evaluate the effect of covariates (age,
Tac concentration (ng/ml) 10.53 ± 4.47 10.61 ± 4.62 9.48 ± 5.59
Dose/concentration (mg/μg/l) 0.019 ± 0.015 0.012 ± 0.009 0.009 ± 0.006 gender, weight, creatinine clearance, post-transplantation time) on
Creatinine clearance (ml/min) 84.7 ± 44.7 97.6 ± 43.6 104.7 ± 51.7 tacrolimus dose requirement. Covariates were dichotomizated
Results are expressed as mean ± SD.
according to the median value in order to investigate which group
Tac = tacrolimus. of age, weight and creatinine clearance or post transplantation period
could affect tacrolimus dose. The best final model was selected using
the Akaike information criterion (AIC).
maintain the whole-blood concentration within the recommended tar-
get range. 3. Results
Concomitant immunosuppressive drugs based on Mycophenolate
3.1. Patients' data
Mofetil and methylprednisolone at a dose of 2000 mg/day and
500 mg/day, respectively, were administered in all patients. Cortico- One hundred and ten Tunisian patients (75 men and 35 women) undergoing renal
steroid dose was progressively reduced to 20 mg/day of prednisone transplantation were included in the study. Their mean age was 31.6 ± 11.9 years and
in day 7, to reach a long-term maintenance dose of 10 mg/day at their mean weight was 58.2 ± 13.8 kg (Table 1).
the end of the second week post-transplantation.
The samples were subdivided according to the post-transplantation 3.2. Correlation between concentration and tacrolimus doses
period into three groups. Group 1 (G1), 2 (G2) and 3 (G3) are blood
A total of 446 blood samples for the determination of tacrolimus trough concentra-
samples collected from patients with a less than 3-month post- tion were obtained during the period of the study. The mean number of samples per
transplantation delay, those with a 3 to 12-month delay and those patient was 8.1, ranging from 1 to 17 samples per patient.
with a more than 12-month delay, respectively. Correlation analyses between trough concentration levels and tacrolimus doses
Blood samples for the determination of trough tacrolimus concen- were performed. No significant correlations were found between blood concentration
and tacrolimus doses either in all samples (Fig. 1A) or in the three groups (Fig. 1B, C, D)
trations were taken immediately prior to the morning dose. C0 was
adjusted according to the target range proposed by the European con-
3.3. Determination of tacrolimus doses corresponding to concentrations within therapeutic
sensus conference on tacrolimus optimization [2]: between 10 and range
15 ng/ml during the first 3 months after transplantation (G1), 8 and
12 ng/ml in the subsequent 9 months (G2) and between 5 and Among 447 Tac samples, 136 (30%) were under the predefined target ranges (85,
10 ng/ml thereafter (G3). 41 and 21 for G1, G2, G3, respectively), 110 (25%) were over target ranges (18, 45
and 47, for G1, G2and G3, respectively) and 200 (45%) tacrolimus concentrations
Tacrolimus blood concentrations were determined by an enzyme
were within therapeutic ranges: 68 in G1, 54 in G2 and 78 in G3 (Fig. 2).
multiplied immunoassay technique (EMIT, V-twin*). The assay's detec- Analyses of concentrations within therapeutic ranges, doses corresponding to
tion limit was 2 ng/ml. therapeutic concentrations, and D/C0 in each group are detailed in Table 2.

A B
35 30
R2 = 0,020 R2 = 0,001
concentration (ng/ml)
concentration (ng/ml)

30 25
25
20
20
15
15
10
10
5 5

0 0
0,00 0,10 0,20 0,30 0,40 0,50 0,00 0,10 0,20 0,30 0,40 0,50
dose (mg/kg/d) dose (mg/kg/d)

C D
35
R2 = 0,023
concentration (ng/ml)

2 30
35 R = 0,026
concentration (ng/ml)

30 25
25 20
20
15
15
10
10
5
5
0 0
0 0,1 0,2 0,3 0,4 0,00 0,10 0,20 0,30

dose (mg/kg/d) dose (mg/kg/d)

Fig. 1. Correlation between tacrolimus doses and blood concentrations: A. Total blood samples; B. Group 1; C. Group 2; D. Group 3.
200 N. Ben Fredj et al. / Transplant Immunology 28 (2013) 198–202

90
80(48%) 78 (55%)
80
68(41%)
70
54 (39%)
60
47 (33%)
50 45 (33%) <TR
39(28%)
40 TR

30 >TR
18(11%) 17 (12%)
20

10

0
Group 1 Group 2 Group 3
*TR : therapeutic range

Fig. 2. Trough tacrolimus concentrations in each group. *TR: therapeutic range.

A univariate analysis including age, gender, weight and creatinine clearance was 8 to 12 ng/ml during the period between 3 months and 1 year, and
performed. No significant differences were found between three groups (Table 2).
5 to 10 ng/ml more than 1 year after transplantation.
In order to evaluate the effect of these parameters on tacrolimus dose requirement,
we performed a multivariate analysis including time post-transplantation, age, gender, Most previous studies having focused on therapeutic drug moni-
weight and creatinine clearance. Only time post-transplantation was found to be a sig- toring of tacrolimus in renal transplant recipients have assessed the
nificant covariate in the final model as shown by stepwise model selection (Table 3). clinical response of patients (i.e. aimed to evaluate graft reject and/
or tacrolimus toxicity) [9–11]. However, only few studies have deter-
mined the daily tacrolimus dose needed to maintain trough concen-
4. Discussion trations within target levels [3–5].
Our study aimed to evaluate dosing regimen of tacrolimus in renal
Tacrolimus is a calcineurin inhibitor which is highly effective in transplant recipients according to post-transplantation period, as de-
preventing acute rejection after solid organ transplantation [6]. How- fined by the last European consensus conference.
ever, this drug presents a narrow therapeutic index and highly vari- Our results showed that only 45% of tacrolimus concentrations
able pharmacokinetics between and within patients, which is were within target ranges and more than 50% of trough blood levels
mainly explained by variability in bioavailability and hepatic metabo- were supratherapeutic, exposing to tacrolimus side effects, or
lism [7]. Thus, therapeutic monitoring is strongly recommended to infratherapeutic exposing to the risk of acute rejection. Moreover,
optimize tacrolimus dosing regimen. no significant correlation was found between tacrolimus doses and
Since its introduction, target tacrolimus blood levels have been de- blood concentrations, which demonstrate that tacrolimus concentra-
fined by trials comparing groups of patients having different concen- tions could not be predicted by weight-adjusted doses.
tration ranges, and optimal levels are concentrations that provide the These findings improve the usefulness of therapeutic drug moni-
lowest risk of acute rejection as well as an acceptable tolerability. Ini- toring in renal transplant recipients regardless of the post-
tially, tacrolimus target concentrations used were as high as 10– transplantation period. In fact, the need for tacrolimus therapeutic
20 ng/ml at the early post transplantation time and 5–10 ng/ml drug monitoring has been well demonstrated previously, justified
later [8]. More recently, new target levels of tacrolimus concentra- by a narrow therapeutic index and a large inter- and intraindividual
tions have been proposed during the last European Conference Meet- variation in tacrolimus pharmacokinetic [6,11].
ing focused on Tacrolimus TDM. Lower levels of tacrolimus In order to optimize tacrolimus dosing regimen, it is necessary to
concentration have been assessed in the early post-transplantation understand the factors that have a significant effect on the pharmaco-
period taking into account the type of adjunctive medication, induc- kinetic parameters. Some previous pharmacokinetic investigations
tion therapy and post transplantation period [2]. According to these showed some controversy regarding the effects of demographic pa-
factors, trough concentration in renal transplant recipients receiving rameters on tacrolimus dose requirements in renal graft recipients.
tritherapy (tacrolimus + MMF + steroids), as in the case of our pa- Hu et al. [12], who performed a study on 30 renal transplant patients,
tients, should range from 10 to 15 ng/ml during the first 3 months, demonstrated that age, sex and body weight could affect tacrolimus
daily dose. Shishido et al. [13] have showed that age could be a deter-
Table 2 minant factor in tacrolimus dosing requirement. In fact, younger
Characteristics of patients with therapeutic concentrations. transplant recipients need higher tacrolimus doses compared to
older patients. This finding was explained by the faster clearance ob-
Group 1 Group 2 Group 3 p
(n = 69) (n = 54) (n = 78)
served in younger patients. Other authors have shown that race is an
additional factor affecting dosing requirement. Fitzsimmons et al. [14]
Dose (mg/kg/day) 0.17 ± 0.05 0.11 ± 0.04 0.06 ± 0.03 b10−2
and Andrews et al. [15] demonstrated that tacrolimus bioavailability
Tac concentration 12.4 ± 1.27 10.12 ± 1.08 7.36 ± 1.35 b10−2
(ng/ml) is significantly lower in black patients than in non-blacks, contribut-
Dose/concentration 0.013 ± 0.004 0.011 ± 0.005 0.009 ± 0.005 b10−2 ing to the higher dosage requirements (~ twice the dose) observed
(mg/μg/l) in black populations.
Age (year) 32.3 ± 12.04 27.8 ± 10.5 35.2 ± 4.9 0.25
Our results showed that neither demographic parameters nor
Gender (M/F) 16/4 8/3 9/3 0.51
Weight (kg) 60.1 ± 10.5 61.2 ± 11.2 65.5 ± 10.7 0.13
renal dysfunction could have specific effects on the pharmacokinetic
Creatinine 99.3 ± 43.07 102.08 ± 43.2 106.8 ± 45.2 0.53 profile and subsequent tacrolimus dosing requirement. In the current
clearance(ml/min) study, post-transplantation period seems to be the only covariate
Results are expressed as mean ± SD. influencing dose requirements. These findings were consistent with
Tac = tacrolimus. those obtained by several previous studies. Hu et al. [12] showed
 N. Ben Fredj et al. / Transplant Immunology 28 (2013) 198–202
Table 3
Effects of covariates (age, gender, weight, creatinine clearance, post-transplantation time) on Tac dose requirement as analyzed with multivariate linear regression.
Dependant variable
Dose (mg/kg/day) 0.17 ± 0.05
Covariates
Age (year) b31a (n = 101)
Gender (M/F) M (n = 141)
Weight (kg) >60 b (n = 100) b60b (n = 101)
Creatinine clearance(ml/min) b60 (n = 47)
Post-transplantation delay (d) b3 M (n = 68)
Tac = tacrolimus.
a
31: median of age.
b
60: median of weight.
that the tacrolimus dose required to keep a therapeutic level should
be lowered along with time. Similarly, Brunet et al. [3] demonstrated
that a continuous dose decrease was needed during the first
3 months after transplantation to maintain tacrolimus trough con-
centration within therapeutic levels.
In our population, the initial dose required to reach a therapeutic
concentration was 0.17 ± 0.05 mg/kg/day during the first 3 months
after transplantation. In the literature, limited data have aimed at
evaluating the initial dose required to maintain an optimal immuno-
suppression. In a study performed on a European population, Undre
et al. [5] showed that the dose required in the first 3 months after
transplantation varied between 0.25 and 0.27 mg/kg/day. In a Japa-
nese study, Sugioka et al. [4] showed that the tacrolimus dose varied
between 0.15 and 0.30 mg/kg/day during the first 3 months after
transplantation. Brunet et al. [3] who performed their study on a
Spanish population, showed that a dose of 0.15 mg/kg/day was nec-
essary to obtain a therapeutic level concentration in the first month,
and should be lowered to 0.076 mg/kg/day in the third month.
We have also showed that a reduction of 36 and 65% of tacrolimus
initial dose during the second (G2) and third period after transplanta-
tion (G3), respectively, was required in order to maintain the concen-
tration level within therapeutic range. This dosing regimen was
different from those reported in two previous studies. Brunet et al.
and Andre et al. showed that a reduction of 48 and 54% of the initial
dose, respectively, was necessary to maintain a therapeutic concen-
tration of tacrolimus 3 months after transplantation. Differences be-
tween these data and ours may be partly explained by the
difference in the therapeutic range of tacrolimus concentration
adopted in each study. Moreover, we calculated the dose/concentra-
tion (D/C) ratio as a useful indicator to investigate the change of ta-
crolimus bioavailability observed according to post-transplantation
delay in our population and to compare tacrolimus dosing regimen
with previous data. Our results showed a negative significant correla-
tion between D/C ratio and post-transplantation period. This corrob-
orates with previous studies [4,16], indicating that tacrolimus
bioavailability increases with post-transplantation time. It is indeed
demonstrated that tacrolimus absorption increases with the recovery
of gastrointestinal function. Furthermore, a decrease of tacrolimus
clearance because of increasing serum albumin concentration with
the recovery of kidney function could explain the increase of tacroli-
mus bioavailability [4].
A ratio of 0.013, 0.010 and 0.009 during the first 3 months, be-
tween 3 months and 1 year, and 1 year after transplantation, respec-
tively, was observed in our population, which was different from
results found in previously published studies performed on different
ethnic populations. Indeed, the Spanish population [3] showed a
0.010 and 0.005 ratio during the first 3 months and between 3 and
9 months post-transplantation, respectively. Undre et al. [5] have
demonstrated that the daily dosage as well as blood concentration
declined significantly according to post-transplantation delay, but
the reduction percentage during the first year after transplantation
201
0.11 ± 0.04 0.06 ± 0.03
β ± sd p
>31a (n = 100) −0.025 ± 0.007 0.41
F (n = 60) −0.005 ± 0.007 0.37
>60b (n = 100) −0.025 ± 0.007 0.86
>60 (n = 154) 0.002 ± 0.008 0.73
3 M–12 M (n = 54) >12 M (n = 78) −0.048 ± 0.003 b10−2
was significantly different between these two parameters (54% and
29% for tacrolimus doses and blood concentrations, respectively).
These authors showed that the D/C ratio in European population
was as high as 0.019 during the early post-transplantation stage and
declined progressively to 0.012 during the period between 9 months
and 12 months.
We hypothesize that these differences in dosing requirement may
be due to an interethnic polymorphism in the expression of tacroli-
mus metabolizing enzymes, i.e. cytochrome CYP3A5 and CYP3A4
[17,18]. It has been demonstrated that there is a strong correlation
existing between CYP3A genotype and tacrolimus dose requirement.
Indeed, patients carrying a CYP3A5*1 or CYP3A4*1B require signifi-
cantly high doses to reach target concentrations. Recently, Elens et
al. [19] have evaluated the influence of a CYP3A4*22 on Tac pharma-
cokinetics in renal transplant recipients. These authors found that this
SNP was associated with a risk of supratherapeutic Tac concentrations
(>15 μg/l) during the first 3 days after transplantation. Moreover, De
Jonge et al. point out the association between the newly discovered
P450 oxydo-reductase (POR)*28 SNP and the increases of tacrolimus
dose requirements in the first year post-transplantation in patients
carrying a CYP3A5*1 allele [20].
In this study, tacrolimus dose requirement was determinate based
on Tacrolimus concentration targets as defined by European Consen-
sus Conference. However, further pharmacogenetic study is required
to evaluate the association between tacrolimus daily dose require-
ments and pharmacogenetic profiles in this cohort of renal transplant.
5. Conclusion
To our knowledge, this study is the first to analyze the dosing regi-
men in Tunisian renal transplant recipients according to the recommen-
dations of the last European conference consensus on tacrolimus
therapeutic drug monitoring.
Acknowledgements
The authors are greatly indebted to Professor Adel Rdissi for his
help with improving the language used in this article.
References
[1] Cheng YL. Therapeutic drug monitoring of tacrolimus. Hong Kong J Nephrol
2005;7:57–8.
[2] Wallemacq P, Armstrong P, Brunet M, Haufroid V, Holt DW, Johnston A, et al. Op-
portunities to optimize tacrolimus therapy in solid organ transplantation: report
of the European Consensus Conference. Ther Drug Monit 2009;31:139–52.
[3] Brunet M, Torregrosa F, Oppenheimer F, Corbella J. Therapeutic drug monitoring
of tacrolimus in kidney transplantation: 9-month follow-up. Transplant Proc
1998;30:4068–9.
[4] Sugioka N, Matsushita A, Kokuhu T, Okamoto M, Yoshimura N, Ito Y, et al. Estima-
tion of minimum whole-blood tacrolimus concentration for therapeutic drug
monitoring with plasma prednisolone concentration: a retrospective cohort
study in Japanese kidney transplant recipients. Curr Ther Res Clin Exp 2006;67:
103–17.
202 N. Ben Fredj et al. / Transplant Immunology 28 (2013) 198–202
[5] Undre NA, Schafer A, European Tacrolimus Multicentre Renal Study Group. Fac-
tors affecting the pharmacokinetics of tacrolimus in the first year after renal
transplantation. Transplant Proc 1998;30:1261–3.
[6] Sukhpreet, Tiwari P. Therapeutic drug monitoring of immunosuppressants: an
overview. Indian J Pharmacol 2007;39:66–70.
[7] Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide
polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin
inhibitors: part I. Clin Pharmacokinet 2010;49:141–75.
[8] Margreiter R. Efficacity and safety of tacrolimus compared with ciclosporin
microemulsion in renal transplantation: a randomized multicenter study. Lancet
2002;352:741–6.
[9] Hedayat S, Kershner RP, Su G. Relationship of whole-blood FK506 concentrations
to rejection and toxicity in liver and kidney transplants. J Biopharm Stat 1996;6:
411–24.
[10] Staatz C, Taylor P, Tett S. Low tacrolimus concentrations and increased risk of
early acute rejection in adult renal transplantation. Nephrol Dial Transplant
2001;16:1905–9.
[11] Mohammadpour N, Elyasi S, Vahdati N, Mohammadpour AH, Shamsara J. A re-
view on therapeutic drug monitoring of immunosuppressant drugs. Iran J Basic
Med Sci 2011;14:485–98.
[12] Hu RH, Lee PH, Tsai MK. Clinical influencing for daily dose, trough level, and rela-
tive clearance of tacrolimus in renal transplant recipients. Transplant Proc
2000;32:1689–92.
[13] Shishido S, Asanuma H, Tajima E, Honda M, Nakai H. Pharmacokinetics of tacroli-
mus in pediatric renal transplant recipients. Transplant Proc 2001;33:1066–8.
[14] Fitzsimmons WE, Bekerskey I, Dressler D, Raye K, Hodosh E, Mekki Q. Demo-
graphic considerations in tacrolimus pharmacokinetics. Transplant Proc
1998;30:1359–64.
[15] Andrews PA, Sen M, Chang RW. Racial variation in dosage requirements of tacro-
limus. Lancet 1996;348:1446.
[16] Antignac M, Barrou B, Farinotti R, Lechat P, Urien S. Population pharmacokinetics
and bioavailability of tacrolimus in kidney transplant patients. Br J Clin Pharmacol
2007;64(6):750–7.
[17] Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ,
Lindemans J, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1
genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacro-
limus. Clin Pharmacol Ther 2003;74(3):245–54.
[18] Roy JN, Barama A, Poirier C, Vinet B, Roger M. Cyp3A4, Cyp3A5, and MDR-1 genet-
ic influences on tacrolimus pharmacokinetics in renal transplant recipients.
Pharmacogenet Genomics 2006;16(9):659–65.
[19] Elens L, Bouamar R, Hesselink DA, Haufroid V, van der Heiden IP, van Gelder T,
et al. A new functional CYP3A4 intron 6 polymorphism significantly affects tacro-
limus pharmacokinetics in kidney transplant recipients. Clin Chem 2011;57:
1574–83.
[20] De Jonge H, Metalidis Ch, Naesens M, Lambrechts D, Kuypers D. The P450 oxidore-
ductase *28 SNP is associated with low initial tacrolimus exposure and increased
dose requirements in CYP3A5-expressing renal recipients. Pharmacogenomics
2011;12:1281–91.