Introduction
Mycophenolate mofetil (MMF) is one of the first-line immunosuppressants typically coadministered with calcineurin inhibitors (CNIs) and corticosteroids to prevent acute rejection in kidney transplant recipients (KTRs) [1,2]. After oral administration, MMF is rapidly hydrolyzed to mycophenolic acid (MPA). MPA is a noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase, which is a rate-limiting enzyme in the biosynthesis of guanine nucleotide. Consequently, it blocks the proliferation of T and B lymphocytes [3]. Although MPA levels are known to have wide inter- and intraindividual variability [4], it is administered at a fixed dose in routine clinical practice. Furthermore, therapeutic drug monitoring (TDM) for CNIs is considered essential in posttransplant protocols, but the role of TDM for MPA has not yet been fully established.
Several previous studies have shown a significant association between TDM for MPA and clinical outcomes in KTRs. Moreover, an area under the curve (AUC)0–12 hr of MPA ranging from 30 to 60 mg × hr/L [5,6] and a trough level (C0) of MPA ranging from 1.0 to 3.5 μg/mL [7,8] were considered optimal therapeutic ranges that can prevent acute rejection or toxicity after kidney transplantation (KT). Considering the current clinical pattern of prescribing a fixed dose of MMF, it is important to determine whether the fixed dose of MMF reaches the therapeutic target in Korean KTRs. In TDM for MPA, MPA AUC0–12 hr is known to be more strongly associated with rejection in KTRs [9], although its measurement is more time-consuming than that of MPA C0. To date, no prospective study involving Korean KTRs has evaluated the association between MMF dose and MPA AUC0–12 hr.
This study aimed to investigate the relationship between fixed-dose MMF and MMF-related adverse events in incident Korean KTRs using TDM for MPA based on both MPA C0 and MPA AUC0–12 hr.
Methods
Study cohort
This open-label, prospective study included 50 de novo KTRs who provided informed consent prior to enrollment. The inclusion criteria were as follows: 1) aged 20–70 years; 2) crossmatch-negative KT and no donor-specific panel reactive antibodies; 3) ABO-compatible KT; and 4) KT only, without other organ transplantation. The exclusion criteria were as follows: 1) active infectious disease; 2) uncorrected ischemic heart disease; 3) hemoglobin level of <7.0 g/dL, leukocyte count of <2,500/mm3, absolute neutrophil count of <1,500/mm3, and platelet count of <75,000/mm3; 4) hypersensitivity to MMF; 5) gastrointestinal disorders that inhibit the absorption of oral drugs; 6) pregnancy, likelihood of becoming pregnant, and no use of appropriate contraception methods; 7) other reasons determined by investigators that make participation in the clinical trial inappropriate; and 8) treatment with enteric-coated mycophenolate sodium (EC-MPS). Immunological, clinical, and biochemical data were obtained during the follow-up period of 24 weeks.
The study protocol was reviewed and approved by the Institutional Review Board of Kyungpook National University Hospital (No. 2015-05-006). All clinical investigations were conducted in accordance with the guidelines of the 2008 Declaration of Helsinki.
Immunosuppressants and therapeutic drug monitoring
All KTRs received MMF, tacrolimus (TAC), and corticosteroids as immunosuppressant therapy and an interleukin-2 receptor blocker or antithymocyte globulin as induction therapy. A fixed dose of MMF of 1.0 to 1.5 g/day every 12 hours was administered based on the physician’s decision. TAC was initially administered at a dose of 0.05 mg/kg every 12 hours, which was then adjusted to maintain the target TAC C0 in the range of 5 to 10 ng/mL. A dose of 500 mg of intravenous methylprednisolone was administered during surgery, which was tapered to 5 mg/day of oral prednisolone after 3 months.
MPA C0 and MPA AUC0–12 hr were measured at 1 and 24 weeks following KT. MPA C0 was measured using particle-enhanced turbidimetric inhibition immunoassay (Siemens Healthcare Diagnostics Inc.). MPA AUC0–12 hr was measured by collecting venous blood samples at 0, 30, and 120 minutes and was calculated as described previously [10]. MPA AUC0–12 hr was estimated using the following formula: MPA AUC0–12 hr = 10.75 + (0.98 × C0 hr) + (2.38 × C0.5 hr) + (4.86 × C2 hr).
Concurrently administered drugs
All KTRs received nystatin for 1 month after KT; valacyclovir for 3 months; and sulfamethoxazole, trimethoprim, and folic acid for 1 year as infection prophylaxis.
Adverse events
Adverse events included the following: 1) biopsy-proven acute rejection (BPAR), 2) allograft failure, 3) viral infection such as BK virus infection (occurrence of BK viremia [≥104 copies/mL] or BK viruria [≥107 copies/mL] or diagnosis of biopsy-proven BK virus nephropathy) or cytomegalovirus (CMV) infection (presence of significant real-time quantitative CMV polymerase chain reaction viral load [≥103 copies/mL] or diagnosis of CMV disease), and 4) cytopenia (leukopenia defined as the total white blood cell count of <4.0 × 103/μL, anemia defined as a hemoglobin level of <10 g/dL, and thrombocytopenia defined as a platelet count of <150 × 103/μL). Other adverse events included viral infections, including herpes zoster and gastrointestinal symptoms wherein other infectious causes were excluded. The occurrence of de novo donor-specific anti-human leukocyte antigen antibodies (DSAs) was also evaluated.
Statistical analysis
Continuous variables were expressed as mean ± standard deviation or median with interquartile range. The differences between groups were analyzed using an independent sampled t test or chi-square test, as appropriate. Linear regression analysis was performed to determine the relationship of body weight (BW)-adjusted MMF dose with MPA C0 and MPA AUC0–12 hr. The ability of MPA AUC0–12 hr to predict adverse events was further analyzed using receiver operating characteristic curves. Statistical analyses were performed using the SAS system for Windows, version 9.2 (SAS Institute). The p-values of <0.05 were considered to indicate statistical significance.
Results
Baseline characteristics
The baseline characteristics of the included KTRs are shown in Table 1. The mean age of the KTRs was 46.8 years, and 62.0% of them were male. Diabetes mellitus was the most common cause of primary kidney disease. Overall, 68.0% of KTRs received living donor kidney transplants, whereas 32.0% received deceased donor kidney transplants. Moreover, 92.0% of KTRs received an interleukin-2 receptor blocker as induction therapy. The estimated glomerular filtration rates (eGFRs) at 1 and 24 weeks were 73.8 ± 30.2 and 69.6 ± 18.3 mL/min/1.73 m2, respectively. TAC trough levels at 1 and 24 weeks were 6.3 ± 2.8 and 5.7 ± 1.6 ng/mL, respectively.
The characteristics of patients whose MPA C0 and MPA AUC0–12 hr were not within the therapeutic range (both low and high) are shown in Supplementary Tables 1 and 2 (available online). At 1 week, a significant difference was observed in eGFR among low, optimal, and high MPA C0 groups (93.3 ± 24.1 mL/min/1.73 m2 vs. 75.7 ± 29.7 mL/min/1.73 m2 vs. 61.1 ± 29.3 mL/min/1.73 m2, p = 0.04). At 1 week, KTRs with a higher MPA AUC0–12 hr had a significantly lower body mass index (BMI; 21.2 ± 2.0 kg/m2 vs. 24.3 ± 4.2 kg/m2, p = 0.003) and BW (57.1 ± 9.5 kg vs. 68.0 ± 14.2 kg, p = 0.03) compared with those with an optimal MPA AUC0–12 hr.
Mycophenolate mofetil dose and mycophenolic acid exposure
The initial fixed dose of MMF of 1.44 ± 0.16 g/day was adjusted in 24 KTRs (48.0%) and then reduced to a mean dose of 1.19 ± 0.31 g/day at 24 weeks after KT (Table 2). Following KT, most KTRs reached the minimum required MPA C0 of 1.0 μg/mL (1 week and 24 weeks: 84.0% and 88.6% of KTRs, respectively) and MPA AUC0–12 hr of 30 μg × hr/mL (1 week and 24 weeks: 100% and 92.8% of KTRs, respectively). Based on MPA C0, there were no significant differences among the three groups in terms of the BW-adjusted MMF dose (mg/kg) at 1 week (high [>3.5], 26.2 ± 4.7; optimal [1.0–3.5], 22.9 ± 5.2; and low [<1.0], 22.7 ± 6.4; p = 0.12) and 24 weeks (high [>3.5], 20.6 ± 7.0; optimal [1.0–3.5], 19.1 ± 3.2; and low [<1.0], 16.6 ± 8.1; p = 0.23). However, based on MPA AUC0–12 hr, significant differences were noted between the two groups in terms of the BW-adjusted MMF dose (mg/kg) at 1 week (high [>60], 27.4 ± 4.5; optimal [30–60], 23.2 ± 5.3; and low [<30], NA; p = 0.03) and 24 weeks (high [>60], 20.6 ± 4.8; optimal [30–60], 18.7 ± 4.3; and low [<30], 11.0 ± 3.7; p = 0.006) (Fig. 1).
The BW-adjusted MMF dose was significantly correlated with MPA C0 and MPA AUC0–12 hr at 1 week (r2 = 0.064, p = 0.04 and r2 = 0.075, p = 0.03, respectively) and 24 weeks (r2 = 0.088, p = 0.03 and r2 = 0.128, p = 0.01, respectively) after KT (Fig. 2).
Mycophenolic acid exposure and adverse events
In total, 14 KTRs (28.0%) experienced MPA-related adverse events, which were predictable based on MPA AUC0–12 hr, with a cutoff level of 46.4 μg × hr/mL (sensitivity of 78.6% and specificity of 52.8%). The AUC of MPA AUC0–12 hr for predicting MPA-related adverse events was 0.647 (Fig. 3). MPA-related adverse events included BK viremia (n = 4), CMV infection (n = 1), leukopenia (n = 3), other viral infections including herpes zoster (n = 3), and gastrointestinal symptoms including diarrhea (n = 3). No BPAR or allograft failure was observed. During the follow-up period, none of the patients developed de novo DSAs.
MPA AUC0–12 hr was significantly higher in KTRs with adverse events than in those without adverse events (56.0 ± 15.5 μg × hr/mL vs. 48.0 ± 10.8 μg × hr/mL; p = 0.04) (Table 3). However, no significant differences in MPA C0 and BW-adjusted MMF dose were observed between the two groups.
Discussion
In this prospective study involving 50 Korean de novo KTRs who received TAC, MMF, and corticosteroids, the current reduced fixed dose of MMF of 1.0 to 1.5 g/day reached the therapeutic range of MPA during the early posttransplant period. Furthermore, the BW-adjusted MMF dose showed significant positive correlations with MPA levels in terms of both MPA C0 and MPA AUC0–12 hr. High MPA exposure was significantly associated with MPA-related adverse events.
Although previous studies have shown a significant association between MPA exposure and clinical outcomes in patients who underwent KT [5–8,11–13], randomized controlled trials on the effectiveness of TDM-guided dosing of MPA have shown inconsistent results [14–17]. A study involving 137 KTRs receiving cyclosporine who were allocated to either a fixed-dose MMF (2 g daily) or concentration-controlled MMF group showed that a higher dose and AUC of MPA in the concentration-controlled arm were significantly associated with fewer treatment failures and acute rejection at 12 months after transplantation [14]. However, a study including 901 KTRs showed no difference in treatment failure or acute rejection between fixed-dose MMF and AUC-based concentration-controlled MMF arms at 1 year after transplantation [15]. Similarly, in a study involving 720 KTRs receiving CNIs, no significant difference in the incidence of treatment failure was observed between the “concentration control using MPA C0” group and “fixed MPA dosing” group at 12 months after transplantation [16]. In particular, TDM-guided dosing of MPA showed no significant advantage in immunologically low-risk KTRs [17]. A meta-analysis recommended against the use of concentration-controlled MMF as a routine practice in KTRs [18]. Based on current evidence, the Transplantation Society consensus indications for MMF TDM are limited to high-risk KTRs; patients with delayed graft function; those who did not receive induction therapy, corticosteroids, or CNIs; and those with CNI minimization [19].
In North American KTRs, MMF is usually administered at a dose of 1 g twice daily [20]; however, in Korean KTRs, it is administered at a dose of 0.5 to 0.75 g twice daily, which is generally a reduced dose. MMF is generally recommended at a dose of 2 g daily in KTRs; however, this is considered when cyclosporine is administered [21]. Enterohepatic recirculation of MPA is less inhibited when TAC is used [22–24]. Thus, MPA exposure in TAC-based immunosuppressant therapy can be significantly higher than that in cyclosporine-based immunosuppressant therapy [22–24]. A reduced MMF dose may be adequate for patients receiving TAC. Most Korean KTRs commonly receive TAC-based immunosuppressant therapy and a reduced dose of MMF. However, it remains unclear whether the reduced MMF dose actually leads to appropriate drug concentration. Considering that TDM-guided dosing of MPA is not routinely recommended, it is important to ensure that this reduced fixed dose reaches the therapeutic target. A significant positive correlation between MPA dosage and MPA C0 was reported in our previous study [11], which was corroborated by another study on Korean KTRs [12]. Compared with previous retrospective studies, this prospective study used both MPA C0 and MPA AUC0–12 hr and demonstrated that the reduced fixed dose of MMF in Korean KTRs generally reaches the optimal therapeutic range. Considering time-dependent variation in MPA pharmacokinetics, the results of this study based on MPA AUC0–12 hr and MPA C0 have the strength of providing more reliable information compared with the results of a study based on MPA C0 alone. This study has clinical significance as it provides evidence regarding the use of a reduced fixed dose of MMF in TAC-treated Korean KTRs with low immunologic risk in a clinical setting where TDM is not routinely applied.
Current studies have shown that a higher MMF dose is associated with a higher MPA AUC0–12 hr, which reduces BPAR [15,16] but increases the risk of additional toxicity [13,25]. The fixed daily MMF dose used in previous studies was 2 to 3 g, which was higher than its clinical dose of 1 to 1.5 g per day in Koreans. Considering that MPA pharmacokinetics, BMI, and BW may differ according to ethnicity, the results of this study in Koreans may have clinical importance. Furthermore, this study analyzed the characteristics of the group outside the optimal range. The higher the MPA AUC0–12 hr, the lower the patient’s BMI and BW. Although there was no statistically significant difference, this trend was confirmed using MPA C0. This result was determined only at 1 week after KT, which may be related to the relatively higher MMF dose at 1 week compared with that at 24 weeks. These results indicate that TAC-treated KTRs with a lower BMI and BW can receive a reduced MMF dose even 1 week after KT.
This study has some limitations. First, only patients in the early posttransplant period were included, and the observation period was relatively short at 24 weeks. Second, as no episodes of BPAR or allograft failure occurred, the role of TDM for MPA in predicting BPAR or allograft loss could not be determined. Third, this study included only Asian populations, potentially restricting its applicability to other ethnicities. Fourth, as this study included patients receiving MMF, no data on the association between fixed-dose EC-MPS and MPA exposure are available. Further studies on TDM for EC-MPS are warranted because EC-MPS is known to be absorbed at a slower rate than MMF, with the time to maximal concentration showing more variation [26,27]. Fifth, although a previous study reported that the method using C1 hr, C2 hr, and C6 hr can reveal the best correlation with MPA AUC0–12 hr [10], the C0 hr, C0.5 hr, and C2 hr values were used to calculate MPA AUC0–12 hr in this study. Although this decision was made to ensure the convenience of the participants and practical implementation of the research, this method may not accurately reflect the actual MPA AUC0–12 hr. However, based on significant positive correlations between the BW-adjusted MMF dose and MPA AUC0–12 hr observed in this study, the MPA AUC0–12 hr calculation method using C0 hr, C0.5 hr, and C2 hr may be clinically acceptable. Sixth, as protocol biopsy was not performed in KTRs with stable kidney function in this study, subclinical acute rejections that can provide valuable information were not evaluated. Seventh, in this study, the MPA AUC0–12 hr was not interpreted as an excellent predictor of MPA-related adverse events in terms of AUC, sensitivity, and specificity. To validate the ability of MPA AUC0–12 hr more reliably to predict MPA-related adverse events, a prospective study with a longer follow-up period and a larger number of KTRs should be performed.
In conclusion, TDM for MPA revealed that a reduced fixed dose of MMF may be safe and acceptable in Korean KTRs with a low immunologic risk who administered a TAC-based regimen after KT. Considering the significant positive correlations between the BW-adjusted MMF dose and MPA concentration, the determination of the appropriate MPA dose based on BW is recommended.
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