Author Affiliations: Center for Liver Cancer, National Cancer Center, 111 Jungbalsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, Korea (Kim SH, Lee SD, Kim YK and Park SJ)

Corresponding Author: Seong Hoon Kim, MD, PhD, Center for Liver Cancer, National Cancer Center, 111 Jungbalsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, Korea (Tel: +82-31-920-1647; Fax: +82-31-920- 2798; Email: kshlj@hanmail.net)

 

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60378-2

Published online May 21, 2015.

 

 

Contributors: KSH proposed the study and wrote the first draft. KSH, LSD, KYK, and PSJ performed research, collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. KSH is the guarantor.

Funding: None.

Ethical approval: This study was approved by the institutional review board of National Cancer Center, Korea.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Once-daily extended-release tacrolimus (Tac-OD) has been introduced as a useful therapeutic option to increase patient adherence to immunosuppressive therapy. This study aimed to evaluate the safety, efficacy and immunosuppressant adherence of conversion from twice-daily tacrolimus (Tac-BID) to Tac-OD in stable adult living donor liver transplant (LDLT) recipients in a single institution.

 

METHODS: Between February and May 2013, Tac-BID was converted to Tac-OD in recipients followed up for at least 12 months after transplantation and without previous rejection episodes. The switching policy was based on a dose ratio of 1:1 with dose adjustment target trough levels at 3-5 ng/mL. Tacrolimus trough levels, laboratory parameters, metabolic disorders, and adverse events were assessed.

 

RESULTS: A total of 229 patients were enrolled in the study. The median age at conversion was 53 years (range 31-73). The median transplant duration was 35.3 months (range 12.0-95.4). During a median follow-up of 13.5 months after conversion, 9 patients returned to Tac-BID because of adverse events. No acute rejection episodes were observed. Of 214 patients still on Tac-OD at 12 months, 12 (5.6%) received a reduced dose and 95 (44.4%) required an increased dose over baseline. Overall adherence was 82.2% at the end of follow-up.

 

CONCLUSION: The conversion from Tac-BID to Tac-OD with similar target trough levels after conversion is safe and effective for long-term stable LDLT patients.

 

(Hepatobiliary Pancreat Dis Int 2015;14:374-379)

 

KEY WORDS: liver transplantation; living donor; immunosuppressive agents; tacrolimus

 

Non-adherence to immunosuppressive regimens remains a leading cause of increased rejection episodes and graft loss in liver transplantation (LT), despite advances in immunosuppressive drugs.^[1] Once-daily extended-release tacrolimus (Tac-OD) has recently been introduced (Advagraf, Astellas Pharma, Tokyo, Japan) to provide more consistent exposure and convenient dosing. Better treatment adherence and quality of life may be expected by Tac-OD formulation administered in the morning. In a large multicenter study, Tac-OD was shown to be therapeutically equivalent to twice-daily tacrolimus (Tac-BID) in de novo LT recipients.^[2] And the conversion from Tac-BID to Tac-OD on a 1 mg to 1 mg total daily dose basis showed comparable safety and efficacy in 69 stable LT recipients of an open-label, multicenter study.^[3]

 

However, few data are available about the conversion in a cohort of pure adult living donor liver transplant (LDLT) patients. The aim of this study was to evaluate the safety, efficacy and immunosuppressant adherence of conversion from Tac-BID to Tac-OD in a cohort of long-term stable adult LDLT recipients in an Asian single institution.

 

 

This was a single institution prospective cohort study conducted with adult patients who underwent LDLT and were followed up as outpatients in the National Cancer Center, Korea. The study was approved by the institutional review board. All patients gave informed consent in accordance with the Declaration of Helsinki 2000. The conversion from Tac-BID to Tac-OD was performed between February and May 2013. The inclusion criteria were as follows: ABO-compatible LDLT recipients with normal liver function and renal function; stable tacrolimus dosage; trough levels within 3-5 ng/mL in the last 3 months; at least 12-month follow-up after transplantation; and no previous rejection episode. The switching policy was based on a dose ratio of 1:1 with dose adjustment based on clinical assessment of the patient and maintenance of whole blood trough levels of target tacrolimus within the predefined range of 3-5 ng/mL. After the conversion, immunosuppression was maintained on Tac-OD alone while other concomitant immunosuppressive therapy was stopped, leading to Tac-OD monotherapy.

 

Tacrolimus trough levels were evaluated on a monthly basis for the first 3 months after the conversion, and every 2 or 3 months thereafter. Blood samples for determination of tacrolimus trough concentrations were collected at each study visit 22-24 hours after the Tac-OD dose of the previous day and before administration of the dose of the same day. The patients were instructed to administer Tac-OD at least 1 hour before food consumption in every morning on a consistent schedule and abstain from foods or drugs that could interact with tacrolimus. Tacrolimus trough concentrations were determined on the Abbott Architect by chemiluminescent microparticle immunoassay.

 

The efficacy endpoint was proportion of patients with death, graft failure and acute rejection during the follow-up period in all patients who received ≥1 dose of study drug.

 

For safety assessment, liver function, renal function as estimated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula,^[4] fasting blood glucose, blood lipid profile, arterial blood pressure, and any adverse event were checked at each outpatient visit.

 

Hypertension was defined as a blood pressure >140/90 mmHg or as the use of antihypertensive treatment.^[5] Diabetes mellitus was defined according to the American Diabetes Association Diagnostic Criteria.^[6] Hyperlipidemia was defined as hypercholesterolemia >240 mg/dL and hypertriglyceridemia >200 mg/dL or as the use of a hypolipidemic treatment. Renal dysfunction was defined as estimated GFR below 60 mL/min.

 

At the end of follow-up, a questionnaire survey was conducted to measure the effect of drug conversion on both adherence to immunosuppressive therapy and patient preference on dose frequency in a day (twice-daily or once-daily) by the interview with the patients who were followed up at our outpatient clinic. An adherent patient was defined as one who has taken the prescribed dosage of Tac-OD every day on dosing time point for the follow-up period. Immunosuppressant adherence was assessed using a 4-item validated questionnaire of the Basel Assessment of Adherence Scale to Immunosuppressives (BAASIS).^[7]

 

All analyses were performed using SAS version 9.1.3 for Windows (SAS institute, Cary, NC, USA). Continuous variables described with median and range or mean±standard deviation. Categorical variables were compared using the Chi-square test. Continuous variables were compared using Student's t test for two and ANOVA for more than two. A P value less than 0.05 was considered statistically significant.

 

 

A total of 229 LDLT recipients were enrolled in the study and received at least one dose of Tac-OD; 214 of the 229 (93.4%) recipients completed at least one year of treatment with Tac-OD with a median follow-up of 13.5 months (range 12.0-15.1) after conversion. During the study, 15 patients (6.6%) led to discontinuation of study treatment due to death (6) and adverse events (9).

 

The patient baseline characteristics are listed in Table 1. The patient population was all Korean and predominately male (76.4%). The median age at the time of conversion was 53 years (range 31-73). The median transplant duration was 35.3 months (range 12.0-95.4). The main indication for LDLT was hepatocellular carcinoma (HCC) (74.2%). The most common comorbidity was hypertension (35.4%).

 

Immunosuppressant therapy prior to study entry consisted of Tac-BID and mycophenolate mofetil in 188 (82.1%) patients and Tac-BID alone in 41 (17.9%). The mean tacrolimus daily dose at baseline before conversion was 1.98±0.61 mg with the mean tacrolimus trough level of 4.27±1.63 ng/mL. The mean tacrolimus trough level decreased to 2.84±1.23 ng/mL one month after conversion on a dose ratio of 1:1 (P<0.027). The blood tacrolimus levels were stabilized in 205 patients (89.5%) within 2 months, and 3 months after conversion, no patient required further dose adjustment and the tacrolimus trough level remained thereafter within the target range throughout the study (Fig.). Of 214 patients who maintained on Tac-OD at 12 months, 12 (5.6%) received a reduced dose and 95 (44.4%) required a dose increase, of whom 61 (28.5%) received at least a 30% increase in dose over baseline. At the end of follow-up, the mean tacrolimus trough level was 4.10±1.92 ng/mL (P<0.867, vs baseline) with a daily dose of 2.31±1.21 mg (P<0.038, vs baseline).

 

There was no acute rejection episode, clinically suspected or biopsy-proven, at any time during the post-conversion follow-up period. Patient survival at 12 months was 97.4% (223/229) and death censored graft survival at 12 months was 100%. During the study period, there were a total of six deaths. Three patients died of metastases from HCC at 5, 7, and 11 months respectively after conversion. One patient died of recurrent gastric cancer approximately 7 months after conversion. Five patients had cancer recurrence or metastasis at the time of study enrollment. The other two deaths occurred 3 and 6 months respectively after conversion due to liver failure caused by recurrent intrahepatic cholestasis that had already been waxed and waned before conversion. Acute rejection was excluded by liver biopsy in these two patients.

 

Liver function, renal function by estimated GFR, glucose and plasma lipids concentration as well as mean blood pressure remained stable during the 12 months follow-up (Table 2).

 

In 9 patients (3.9%), nine adverse events led to discontinuation of study treatment within 3 months after conversion. They returned to Tac-BID and the switch back was due to diarrhea (3 patients), dizziness (2), tremor (2), diabetes mellitus (1) and asthenia (1). Of the 9 patients, 2 received a reduced dose and 5 received an increased dose. But, the tacrolimus trough level was maintained within the targeted range of 3-5 ng/mL in all of the 9 patients.

 

The prevalence of diabetes mellitus didn't make a statistically significant difference between before conversion and at the end of follow-up (18.3% vs 19.5%, P=0.892). The prevalence of hypertension, hyperlipidemia and renal dysfunction remained unchanged after conversion (35.3%, 16.2% and 3.5%, respectively). In 8 patients with a baseline renal dysfunction (GFR<60 mL/min), renal function remained stable (51±12, 51±23, 52±16, 52±21 mL/min at baseline, 1, 3, 12 months, respectively; P=0.493). Of 170 patients with HCC, four (2.4%) developed HCC recurrence at 5, 6, 8 and 10 months respectively after conversion.

 

The data were collected from 208 (90.8%) of the 229 patients. The overall non-adherence reported on at least one of the four queried items was 17.8% at the end of follow-up after conversion (Table 3). Timing non-adherence was the most common form with patients taking their dose with a delay of more than 2 hours. But, only three patients reported dose reduction. For patient preference on dose frequency, 201 (96.6%) patients provided the response of "Preference to Tac-OD". The response "No preference to either Tac-OD or Tac-BID" was selected by 7 (3.4%) patients. No patients showed preference to Tac-BID.

 

 

This prospective cohort study in the 229 stable LDLT recipients, the first observational trial on Tac-OD in Korea, demonstrated that patients can be successfully converted from Tac-BID to Tac-OD, while maintaining efficacy and safety. There was no acute rejection episode. This can be compared to the low incidence (1.8%) of acute rejection observed in a retrospective single-center study including 394 patients.^[8] Of the 229 patients, 15 (6.6%) had to discontinue study treatment within one year follow-up. Six of the 15 patients were due to death. The causes were preconversion events such as cancer recurrence or cholestasis. These deaths were therefore not related to study drug. The actual switch back from Tac-OD to Tac-BID due to study drug-related adverse events occurred in 9 patients (3.9%). On the basis of incidence over time, there was no indication of an increased risk of renal dysfunction, liver dysfunction, diabetes mellitus, hyperlipidemia, or hypertension during the course of the study. These results suggested that a target tacrolimus trough level of 3-5 ng/mL minimized drug-related adverse events without compromizing the prophylaxis for rejection. Though there was no control group in this study, these findings are consistent with those observed in previous studies on Tac-OD.^{[3, 9]}

 

In this study, the patients were adult LDLT recipients and nearly three-quarters of them had HCC at the time of the transplantation, reflecting the status of the National Cancer Center. In this series, 4 patients (2.4%) had HCC recurrence within one year after conversion. A study^[10] found that overexposure to tacrolimus increased the risk of HCC recurrence after LT, where the trough level of tacrolimus was 11.6±1.5 ng/mL in patients with recurrence and 8.6±1.7 ng/mL in those without recurrence with an optimal cut-off value of 10 ng/mL. In our study, however, the trough levels were maintained within the range of 3-5 ng/mL and HCC recurrence occurred in 4 patients over one year after LDLT, who had tumors beyond the Milan criteria at the time of LDLT. HCC recurrence was therefore most likely due to advanced tumor stage rather than immunosuppression.

 

The important potential limitation of this study includes the absence of tacrolimus blood level within 1 month after immunosuppression conversion. Systemic exposure to Tac-OD was 50% lower than exposure to Tac-BID during the first week after LT, and significant dose adjustment was required to achieve similar tacrolimus exposure.^{[2, 11]} A prospective observational study^[12] reported that close monitoring of target trough levels is essential in the early period after conversion even in stable recipients. However, stable recipients were followed up one year after LDLT in our outpatient clinic every 6 or 8 weeks. Most patients in our study were reluctant to pay more follow-up visits even though they preferred once daily dose. When the patients had at least one year follow-up after LDLT and stable liver function, tacrolimus trough levels were monitored in the outpatient clinic once a month for the first 3 months after conversion, and every 2 or 3 months thereafter according to routinely scheduled follow-up visits before conversion. We found that the trough levels were stabilized within 3 months from conversion and remained thereafter within the target range throughout this study with no further dose adjustment required. These findings showed that dose adjustment could be achieved by once a month follow-up for the first 3 months after conversion in stable LDLT patients with at least one year follow-up without compromizing safety and efficacy of Tac-OD.

 

In this study, we also observed that upon conversion on a 1:1 mg basis, increased dose was required to maintain equal trough levels in 44.4% of 214 patients on Tac-OD at 12 months after conversion. Of the patients, 28.5% received at least a 30% increase in dose over baseline and 5.6% received a reduced dose. The daily dose tacrolimus remained stable after dose adjustment while the mean trough levels were lower after conversion to once-daily dose. The results are consistent with those of 19 LT recipients reported in a recent study.^[13] A study^[14] on the role of ethnicity showed that significantly higher doses of both Tac-BID and Tac-OD were required in non-Caucasians to achieve equivalent serum concentrations, and that 27.5% of east Asians required a dose increase of >30% in stable renal transplant recipients undergoing conversion from Tac-BID to Tac-OD.^[15] Furthermore, food retention in the gastrointestinal tract, fat meal content, and circadian variations in tacrolimus absorption and disposition may be contributing factors for altered tacrolimus concentrations after conversion.^{[16, 17]} The better understanding of drug dosages and resultant drug concentrations upon switching to the Tac-OD formulation in terms of relation with the above-mentioned factors is beyond the scope of this study. More research is needed to investigate whether the trough level can be lowered below the current one without an increased risk of rejection. The reduced daily dose can lead to less likelihood of the drug-induced adverse events.

 

Adherence to immunosuppressive therapy is a critical issue among transplant recipients. Korean reports on non-adherence in LT are limited. Lack of adherence can be caused by multiple daily doses.^[18,19] The present study included a large-scale survey on treatment adherence and preference on dosing frequency in LDLT recipients in a single institution of Korea. The results of this study showed that 90.8% patients responded completely to adherence after conversion and 96.6% of patients preferred Tac-OD to Tac-BID. Additionally, immunosuppression was maintained on Tac-OD alone after conversion. The concomitant immunosuppressive therapy, mycophenolate mofetil, used twice daily in 82.1% of the patients prior to study entry was stopped, which implied that there is no need for an additional evening dose. Therefore, the high adherence and preference in our study can be attributed to the four factors; once daily dose medication, the stop of concomitant immunosuppressive therapy, the low rate of adverse events, and less frequent follow-up visits within the study setting during the early period after conversion.

 

In conclusion, the conversion from Tac-BID to Tac-OD with similar target trough levels after conversion is safe and effective for long-term stable LDLT patients.

 

 

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