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Volume: 12 Issue: 4 August 2014


Conversion From Twice-Daily to Once-Daily Extended-Release Tacrolimus in Renal Transplant Recipients: 2-Year Results and Review of the Literature

Objectives: Tacrolimus extended-release formulation has been approved for use in Canada since October 2008. In initial studies, efficacy and safety profile were demonstrated as similar for both formulations (twice-daily tacrolimus and extended-release formula tacrolimus). To validate the safety and efficacy of extended-release formula tacrolimus, we conducted a prospective observational study.

Materials and Methods: At our institution, between January 2009 and January 2010, the switch from tacrolimus to extended-release formula tacrolimus was done in 130 stable kidney recipients. Clinical data were accessed at baseline (data before conversion), 1 to 2 weeks, 1 month, 3 months, 6 months, 12 months, and 24 months after conversion.

Results: One hundred thirty renal transplant recipients were included in the current study. During the observation period, we saw no acute rejection and no change in graft function (mean serum creatinine levels remained stable). However, compared with baseline, mean tacrolimus trough levels were significantly reduced at 1 to 2 weeks, at 1 month, 6 months, 12 months, and at 24 months after conversion. Regarding the safety profile, no significant changes were noted in blood glucose, potassium, and magnesium. Approximately 35% of recipients preferred the extended-release formula tacrolimus to twice-daily tacrolimus.

Conclusions: Conversion from twice-daily tacrolimus to extended-release once-daily tacrolimus appears to be safe and convenient up to 2 years after conversion in some recipients.

Key words : Immunosuppressive agents, Immuno-suppression, Kidney transplant, Patient compliance, Calcineurin inhibitor


According to the Canadian Organ Replacement Register data, although short-term graft survival is excellent, long-term graft survival is around 80% at 5 years posttransplant (deceased donor).1 Noncompliance to medication can contribute to chronic rejection and chronic graft dysfunction. To improve compliance, many strategies have been used including patient education, close follow-up, and reduction of medication pill burden. Today, calcineurin inhibitors represent the backbone of modern immunosuppression, particularly tacrolimus, usually prescribed twice daily. Since October 2008, the tacrolimus extended-release (ER) once-daily (OD) formulation has been approved for use in Canada. Initial studies demonstrate that both formulations are similar in terms of efficacy and safety profile.2-3 The OD formulation was developed to simplify dosing regimens and optimize patient compliance. To evaluate the efficacy and safety of conversion from the usual twice-daily to the OD ER tacrolimus, we conducted a single-center observational cohort study and review the literature.

Materials and Methods

At the Maisonneuve-Rosemont Hospital in Montreal, Canada, the usual maintenance immunosuppression for kidney transplant recipients includes the following 3 agents: a calcineurin inhibitor (mainly tacrolimus, twice daily), prednisone, and an anti-metabolite (such as mycophenolate mofetil). Depending on immunologic risk, some recipients are initially induced with an IL-2 receptor antagonist or a lymphocyte-depleting agent. To patients with a stable graft transplant (> 3 mo posttransplant without rejection), we proposed treating them with tacrolimus twice-daily converted to OD ER tacrolimus with a conversion ratio of 1:1 (mg:mg). We followed a select cohort of recipients > 2 years posttransplant, as the tacrolimus target level in this group would remain stable (target trough level of 4-5 ng/L). Clinical data were assessed at baseline (time of medication switch), 1 to 2 weeks, 1 month, 3 months, 6 months, 12 months, and 24 months after conversion. At these times, we collected tacrolimus doses, tacrolimus trough levels, blood pressure (only at baseline and 3 mo), graft function, lipid profile, and blood glucose, potassium, and magnesium levels. After 6 months after conversion, a satisfaction questionnaire was given to all patients.

To compare between baseline and after treatment, we used paired t test for normally distributed data and the signed rank test for all other data. A P value < .05 was considered statistically significant. All data were analyzed using SAS software (version 9.2, SAS Institute, Inc., Cary, NC, USA).


There were 130 patients in the study. Baseline characteristics of patients are summarized in Table 1. There were more men in the cohort (56%); the mean age was 53 years old, and 33% of patients were diabetic. Mean time from transplant to conversion was 5.4 years and mean baseline creatinine level was 118 μmol/L.

After conversion, graft function remained stable over 2 years (Figure 1). However, when compared with baseline, mean tacrolimus trough levels were significantly reduced at 1 to 2 weeks, 1 month, 3 months, 6 months, 12 months, and at 24 months after conversion (Table 2). The tacrolimus levels seemed to fall within a month after conversion and remained stable afterwards (Figure 2). The mean dosage of ER tacrolimus was slightly higher at 6 months compared with baseline (3.7 mg vs 3.5 mg). At 3 months after conversion, only 56% of patients had the same dosage as they did at baseline. The baseline dosage had to be increased in 28%, and reduced in 16%, of the remaining patients (Figure 3). Most of the adjustments were minor changes (± 0.5 mg, Table 3). Despite this reduction in tacrolimus levels, only 3 patients developed acute rejection during follow-up.

No significant change was noted in the metabolic profile including blood glucose, potassium, and magnesium up to 2 years after conversion. Interestingly, the diastolic blood pressure appeared to be significantly lower at 3 months after conversion (-3 mm Hg; P = .03), but not the systolic blood pressure. The satisfaction questionnaire showed that 35% of recipients preferred ER tacrolimus. However, up to 45% of patients had no preference (Figure 4).


After converting from twice-daily tacrolimus to ER tacrolimus (mg per mg), our results suggest that the level of tacrolimus in the blood may drop compared with the baseline level and could remain low for up to 2 years. These findings are consistent with other observational studies.4-6 It seems that a higher dosage of tacrolimus is required to achieve the same tacrolimus level as baseline. However, in stable transplant recipients, as the tacrolimus target trough levels are kept between 4 and 6 ng/mL, dosage modifications are usually not necessary or are minor. In our study, only 28% of recipients needed a higher dosage at 3 months compared with baseline.

Regarding the safety profile, switching from tacrolimus twice-daily to OD appears to be safe, as the graft function and the metabolic profile remained stable up to 2 years. Only 3 rejections occurred late after conversion and were probably not related to switching, as no acute rejection was reported within the first year after conversion. Only one-third of recipients were satisfied with ER tacrolimus (mainly because it is taken OD), and almost half of the patients saw no benefit. This observation might be explained by the pre-existing pill burden: 1 less pill would not make a big difference for these patients.

Extended-release tacrolimus is used as mainte-nance immunosuppression for de novo kidney transplants and also in long-term stable kidney transplants. In 2007, in a phase 3 randomized trial that included 638 de novo kidney recipients, long-acting tacrolimus was compared with tacrolimus and cyclosporine as part of a mycophenolate mofetil-based immunosuppression.7 At 12 months posttransplant, there was no difference in the primary combined endpoint of death, graft loss, and incidence of rejection. More recently, Krämer and associates published another phase 3 double-blind randomized study in which 667 new kidney recipients received either OD or twice-daily tacrolimus combined with steroids and low-dose mycophenolate.8 In the per-protocol analysis, the incidence of biopsy-proven acute rejection was slightly higher with tacrolimus OD over 24 weeks (20.4% vs 15.8%; not significant). Graft function, graft loss, patient survival, and adverse reaction profiles were similar among the 2 groups.

In a few observational cohort studies similar to our study, stable kidney transplants were switched from twice-daily to OD tacrolimus to enhance medication compliance. The results suggest that graft function remains stable after conversion without an increased risk of acute rejection. However, decreased blood levels of tacrolimus were sometimes observed. The efficacy and safety of ER tacrolimus also has been demonstrated in other solid-organ transplants. Van Hooff and associates reported their 4-year experiences with OD tacrolimus in phase 2 conversion studies and in de novo kidney, liver, and heart transplants. They showed that ER tacrolimus has a similar efficacy and safety profile up to 4 years after transplant compared with twice-daily tacrolimus.9 Trials are summarized in Table 4.4-11

We were one of the first transplant centers in Canada to switch twice-daily to OD ER tacrolimus in stable kidney transplants who had been followed-up for 2 years. Despite the observational nature of our study and the absence of a control group, we demonstrated that conversion to ER tacrolimus was safe and convenient in one-third of kidney transplant recipients. These observations are similar to previous published studies.4-11 We usually do not use ER tacrolimus as induction in de novo kidney transplants as the dosage of tacrolimus is easier to adjust with the twice-daily formulation. However, OD tacrolimus can be useful in patients in whom we want to decrease the initial exposure to calcineurin inhibitors (eg, severe acute tubular necrosis).

In conclusion, our study results suggest that despite a mild potential decrease in tacrolimus blood level, conversion from twice-daily to OD tacrolimus appears to be safe and convenient for some stable recipients up to 2 years after conversion. This formulation might be useful as a strategy to improve adherence.


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Volume : 12
Issue : 4
Pages : 323 - 327
DOI : 10.6002/ect.2013.0165

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From the 1Division of Nephrology, Maisonneuve-Rosemont Hospital; and the 2Department of Medicine, University of Montreal, Montreal, Quebec, Canada
Acknowledgements: The authors have no conflicts of interest to disclose. The study was partially funded by Astellas, but they did not participate in the data analysis, writing, or review of the paper. The study was also funded by the Maisonneuve-Rosemont Hospital Foundation (La Néphrologie et son Impact).
Corresponding author: Duy Tran, MD, Maisonneuve-Rosemont Hospital, 5415 Boul. De l’Assomption, Montréal, Québec, Canada, H1T 2M4
Phone: +1 514 252 3489
Fax: +1 514 252 3026