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.