DISCUSSION
The safety and efficacy of twice-daily and once-daily tacrolimus in
liver transplant recipients were shown to be
similar.3,10,14-16 Several previous studies
demonstrated that liver dysfunction is the most common adverse event
after converting from twice-daily to once-daily
tacrolimus.11 In our present study, the incidence of
liver dysfunction in stable liver transplant recipients converted to
once-daily extended-release tacrolimus was higher in the CYP3A5expressor group than in the non-expressor group. However, the between
group difference was not statistically significant. None of the study
patients experienced acute rejection or graft failure, and no mortality
was observed in our series. In previous studies, CYP3A5expression was shown to be associated with a significant increase in the
risk of biopsy-proven acute rejection and tacrolimus-induced
nephrotoxicity at three months post-transplant,17 and
with a decrease in eGFR at three months after renal
transplantation,18 However, our present study did not
demonstrate a significant difference in renal function in CYP3A5expressors and non-expressors.
After 1:1 conversion from twice-daily to once-daily extended-release
tacrolimus, the trough level of the drug in stable adult liver
transplant recipients decreased by nearly 25%. Up to 25% of the
patients required a tacrolimus dose increase after the conversion. These
findings are consistent with the results of other once-daily tacrolimus
conversion studies in LT patients,9-11,16 A 15-20%
increase in the daily dose of tacrolimus has been suggested in order to
achieve the same target trough level of the drug following the
conversion.19
CYP3A5 expression was shown to influence tacrolimus exposure,
with the exposure in CYP3A5 expressors receiving either
twice-daily tacrolimus or once-daily tacrolimus being lower than in the
non-expressors.6-8,14 CYP3A5 expressors carry
the *1 variant which encodes the functional enzyme responsible
for the metabolism of tacrolimus; therefore, they may require a higher
dose of tacrolimus than the non-expressors to achieve the target trough
level of the drug.3-5 Our present study demonstrated
that CYP3A5 polymorphism influenced both tacrolimus dose and
trough level of the drug; the median dose of tacrolimus both before and
after switching to the once-daily extended-release formulation was
significantly higher in the expressor group than in the non-expressors.
This observation is also consistent with the results of previous studies
in which CYP3A5 expressors, both adult and pediatric patients,
required higher doses of tacrolimus due to higher oral clearance of the
drug.20,21 Our present study showed that the decrease
in the trough level of tacrolimus was greater in the expressor group
than in the non-expressors, also after adjustment for patient weight and
tacrolimus dose. CYP3A5 genotype is known to play a role in
determining the effect of interacting drugs, such as fluconazole, on
tacrolimus pharmacokinetics.5 However, it needs to be
stressed that our study did not analyze the issue of drug interaction,
and all patients who received agents that might potentially interact
with tacrolimus were excluded from the analysis.
While we did not find a significant difference in the incidence of AEs
in the expressors and non-expressors, the frequency of drug-related AEs
was higher in the former group. This was likely associated with a higher
dose of tacrolimus received by the expressors. In view of this
observation, a higher dose of tacrolimus might be a confounder in
previous studies analyzing the link between CYP3A5 genotype and
nephrotoxicity risk, especially given that our present study did not
demonstrate a significant CYP3A5 genotype-related difference in
the occurrence of renal dysfunction. In a recent study, Korean adult
liver transplant recipients with CYP3A5 expression presented with
low peripheral blood CD4+ adenosine triphosphate (ATP) immune response
activity despite maintaining a constant concentration of tacrolimus, and
suffered from infecĀtious complications.22 In
contrast, the incidence of infectious complications in our present study
was lower in the expressor group than in the non-expressor group (7.1%
vs. 18.3%), and no severe infections were recorded among the
expressors.
Correlation between Cmin of tacrolimus and the effects of the drug is
known to be stronger than the dose-effect correlation23. Because of a strong correlation between Cmin and
systemic exposure (AUC), the dose of tacrolimus can be tailored using
the Cmin level as a surrogate marker of exposure.3Monitoring of Cmin is mandatory to minimize the risk of rejection (Cmin
below the target range), as well as to reduce the risk of
nephrotoxicity, and, to a lesser extent, neurotoxicity (Cmin above the
target range).3,14 In present study, the AUC for
twice-daily tacrolimus did not differ significantly from the AUC for
once-daily tacrolimus, despite a lower Cmin for the latter. This implies
that the same target trough level of tacrolimus cannot be used to
predict the efficacy of the drug (AUC) after the conversion, especially
among the expressors. In the non-expressor group, Cmin correlated
significantly with AUC, whereas a significant correlation between Cmax
and AUC was observed in the expressor group. Genetic polymorphisms are
known to influence drug metabolism and have been implicated as a cause
of individual variability in drug pharmacokinetics. A difference inCYP3A5 protein expression level in the small intestine, and
replacement of croscarmellose with ethylcellulose may influence the oral
bioavailability of tacrolimus in both initial exposure and steady state.
Therefore, the diffusion rate of tacrolimus after administration of its
once-daily formulation leads to a prolonged release of the drug. In our
present study, the absorption of once-daily tacrolimus in CYP3A5non-expressors was slower compared with the twice-daily formulation.
In a previous study, conversion from twice-daily to once-daily
tacrolimus was associated with a 21% decrease in the median drug
exposure in CYP3A5 expressors. Based on that observation,
approximately a 1.25-fold increase in total daily tacrolimus dose was
recommended in CYP3A5 expressors after switching to the
once-daily formulation, to maintain the same level of tacrolimus
exposure.24 However, the results of our present study
imply that the dose adjustment might not be necessary since, in the
expressor group, the AUC after conversion to the once-daily
extended-release tacrolimus did not differ significantly from that after
the conversion, and unlike in the non-expressors, the AUC correlated
with Cmax, rather than with Cmin.
This study has several limitations. First, the sample size was
relatively small, and the follow-up period was quite short. Hence,
further large-scale studies are needed to determine whether the events
occurring during the post-transplant period might have an adverse effect
on the long-term outcome in liver transplant recipients. Second,
although we compared the incidence of liver dysfunction in the expressor
and non-expressor groups, reducing the drug concentration in this study
increased the tacrolimus dose given by the physician to maintain an
adequate trough level, which limits the analysis. Therefore, it was
difficult to determine the true incidence of liver dysfunction. Third,
our study was conducted with Koreans. Therefore, our results cannot be
generalized to patients in Western countries. Fourth, the
pharmacokinetic analysis included only ten patients, and previous
studies documented a considerable intra- and interpatient variability in
the pharmacokinetics of tacrolimus delivered in either twice-daily or
once-daily formulations.19,25,26 Hence, the effects ofCYP3A5 gene polymorphism on tacrolimus pharmacokinetics need to
be verified in a larger group of liver transplant recipients. Fifth, we
did not know the CYP3A5 gene status of liver donors. Unlike in
other organ transplantations, the liver transplant does not need to
share the genetic background of the recipient. As the activity of most
drug-metabolizing enzymes is very elevated in the liver, polymorphism of
the CYP3A5 gene, whether in the recipient or the donor, would
likely contribute to individual variance in drug pharmacokinetics.
In conclusion, the results of the present study suggest that
determination of the CYP3A5 genotype in liver transplant
recipients might be helpful in both prediction of tacrolimus
pharmacokinetics after conversion to once-daily extended-release
tacrolimus formulation. After the conversion, CYP3A5 expressors
showed a more evident decrease in the trough level of tacrolimus (Cmin)
than the non-expressors. However, the pharmacokinetic analysis did not
show a significant difference in the AUC before and after the
conversion. The AUC in CYP3A5 expressors switched to once-daily
tacrolimus correlated with Cmax, rather than with Cmin. This implies
that CYP3A5 expression might have a greater influence on the
pharmacokinetics of once-daily tacrolimus than the twice-daily
tacrolimus formulation.
The clinical relevance of the findings presented above needs to be
verified in further large-scale studies analyzing various
pharmacogenetic strategies for tacrolimus dosing and the effect ofCYP3A5 genetic polymorphism on long-term outcomes in liver
transplant recipients.