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Conversion From Twice-Daily to Once-Daily Tacrolimus in Stable Liver Transplant Patients: Effectiveness in a Real-World Setting
Conversion From Twice-Daily to Once-Daily Tacrolimus in Stable Liver Transplant Patients: Effectiveness in a Real-World Setting G. Valente, L. Rinaldi, M. Sgambato, and G. Piai
ABSTRACT Background. The prolonged-release once-daily (QD) tacrolimus is a formulation developed to improve adherence to immunosuppressant (IS) regimen, reducing the frequency of dosing, and to increase safety, avoiding toxic peak concentrations. We evaluated efficiency and quality of conversion from twice-daily (BID) to QD tacrolimus formulation in stable liver transplant (LT) recipients in the real-setting of a gastrohepatology team peripheral to LT centers. Patients and methods. Thirty-four LT recipients (median age 60 years, range 33– 69) were switched from BID tacrolimus to QD tacrolimus (1:1 dose) at a median of 38 months (range 8 –211) after transplantation. Tacrolimus levels and laboratory analyses were recorded before and postconversion. Adherence to IS treatment was measured by a modified “Basel Assessment of Adherence Scale to Immunosuppressives.” Results. Median postconversion follow-up was 21 months (range 6 –35, at least 12 months in 30 patients). Mean total tacrolimus daily dose and mean tacrolimus trough level were not significantly different before and after the switch (3.1 ⫾ 2.3 preconversion versus 3.1 ⫾ 2.5 and 3.0 ⫾ 2.5 mg at 6 and 12 months postconversion, respectively; and 5.3 ⫾ 1.8 preconversion versus 4.6 ⫾ 1.4 and 4.5 ⫾ 1.8 ng/mL at 6 and 12 months postconversion, respectively). All patients maintained stable liver and metabolic parameters. Renal function by glomerular filtration rate increased (67 ⫾ 17 preconversion versus 73 ⫾ 19 and 73 ⫾ 20 mL/min at 6 and 12 months postconversion, respectively; P ⫽ .003). No acute rejection episode or major severe adverse events occurred postconversion. Patientreported outcome showed a reduction of missed IS doses. Conclusion. We observed that in a real-world setting far from LT centers, the switch from BID tacrolimus to QD tacrolimus in stable LT recipients is efficient (safe and effective) to improve quality of medical care, with possibly better IS adherence and improvement of renal function. ACROLIMUS (TAC) is an immunosuppressive agent widely used to prevent allograft rejection in organ transplantation.1 An extended-release formulation of TAC has been recently developed as alternative to standard immediate-release formulation, allowing once-daily (QD) instead of twice-daily (BID) dosing, with evidence of similar safety and efficacy profiles.2,3 It is well known that nonadherence to immunosuppressant regimen, associated often to the complex and long-term treatments, results in a poor liver transplant (LT) recipient outcome.4,5 Also, renal failure is an important posttransplant cause of morbidity and mortality6 and so it is necessary to minimize the risk of
T
drug-related nephrotoxicity while maintaining a sufficient dosage to prevent rejection. Reducing the frequency of immunosuppressive dosing may improve adherence to ther-
From the UOSD Fisiopatologia Epatica con Servizio di Assistenza ai Trapiantati e Trapiantandi Epatici, AORN Sant’Anna e San Sebastiano, Caserta, Italy. Address reprint requests to Giovanna Valente, UOSD Fisiopatologia Epatica con Servizio di Assistenza ai Trapiantati e Trapiantandi Epatici, AORN Sant’Anna e San Sebastiano, Via Gennaro Tescione, 1, 81100 Caserta, Italy. E-mail: giovannavalente1977@ libero.it
© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2013.02.021
Transplantation Proceedings, 45, 1273–1275 (2013)
1273
1274
apy and at the same time may reduce the toxicity also due to BID TAC peak levels.7 In this study we evaluated effectiveness of the switch from BID to QD TAC formulation, investigating the effects of conversion on immunosuppressive adherence and renal function in stable LT recipients in the real-world setting of a gastrohepatology team peripheral to LT centers. PATIENTS AND METHODS This was an observational study conducted during the daily activities in adult LT recipients in a gastrohepatology clinic of a hospital that is not within a transplant center. The switch from BID to QD TAC regimen was based on 1:1 mg proportion and patients were converted if they had at least 8 months’ posttransplant follow-up, no acute rejection episodes in the last year, and BID TAC dose stable for at least 12 weeks prior to conversion. During follow-up, TAC doses were adjusted to maintain within the target trough concentration (3 to 6 ng/L). TAC trough levels, liver and renal function, and metabolic parameters were regularly recorded before conversion, 10 days after conversion, again on average every 2 months or whenever it was necessary. Renal function was evaluated by estimated glomerular filtration rate (eGFR) using the modified Modification of Diet in Renal Disease formula.8 Clinical evaluation, adverse events, and results of laboratory values were assessed at each visit. Patient-reported outcomes (PROs) on adherence to immunosuppressant therapy were assessed at baseline and at month 6 by a modified “Basel Assessment of Adherence to Immunosuppressive medication scale” (BAASIS Scale), consisting of a questionnaire administered to the patient in the form of interview.9 This instrument, using four items, explored “taking” (dose not taken), “skipping” (several dose repeatedly not taken), “timing” (dose taken with more than 2 hours’ delay), and “dose reduction” (without counsel of clinician), referring to the last 4 weeks. Also a visual analog scale (VAS) ranging from 0 (immunosuppressant never taken as prescribed) and 100 (always taken as prescribed) allowed patients to estimate their adherence to prescribed medication in percent. Finally, all patients expressed their preference to the once- or twice-daily regimen. The administration of the questionnaires was entrusted to our charge experienced nurse (M.S.). Informed consent was obtained from each patients.
Statistical Analysis The results are presented as mean ⫾ standard deviation or median (range) for continuous variables and percentage for categorical variables. Paired data were analyzed with a paired t test. Statistical significance was defined as a P value of less than .05. All statistical analyses were performed with Statistical Package for Social Sciences software (version 16, SPSS, Inc, Chicago, Ill, USA).
RESULTS Patients’ Characteristics at Baseline
The main baseline characteristics of liver transplant recipients are shown in Table 1 Between April 2009 and May 2011, 27 men and 7 women, median age 60 years (range 33– 69), with a posttransplantation period of a median of 38 months (range 8 –211), were switched from BID TAC to QD TAC. Immunosuppressant therapy was prevalently based on TAC in association with mycophenolate mofetil (n ⫽ 20, 59%).
VALENTE, RINALDI, SGAMBATO ET AL Table 1. Patients’ Baseline Characteristics Patients (n ⫽ 34)
Variables
Age, y (median, range) Gender (M/F) Months from transplantation (median, range) Postconversion follow-up, mo (median, range) Patients with at least 12 mo of follow-up Immunosuppression Tacrolimus monotherapy Tacrolimus ⫹ mycophenolate mofetil Tacrolimus ⫹ sirolimus Comorbidities Renal dysfunction (eGFR ⬍ 60 mL/min/1.73 m2) Diabetes mellitus Arterial hypertension Dyslipidemia
60 (33–69) 27/7 38 (8–211) 21 (6–35) 30 (88%) 13 (38%) 20 (59%) 1 (3%) 6 (17%) 5 (15%) 16 (47%) 8 (23%)
Abbreviations: eGFR, estimated glomerular filtration rate.
After the Switch to QD-TAC
Median postconversion follow-up was 21 months (range 6 –35), with at least 12 months in 30 patients. Mean TAC level (ng/mL) was 5.3 ⫾ 1.8 preconversion, with a BID dose of 3.1 ⫾ 2.3 mg. During the first 6 months, TAC dose was modified ⬎ ⫾20% of starting dose, increasing in 5/34 and decreasing in 5/34 LT recipients, in order to remain in therapeutic range. At 6 and 12 months, mean TAC levels were 4.6 ⫾ 1.4 and 4.5 ⫾ 1.8, with mean QD doses (mg) of 3.1 ⫾ 2.5 and 3.0 ⫾ 2.5, respectively. During the follow-up all patients maintained stable liver and metabolic parameters. Renal function by eGFR slightly but significantly increased (67 ⫾ 17 preconversion versus 73 ⫾ 19 and 73 ⫾ 20 mL/min at 6 and 12 months postconversion, respectively; P ⫽ .003). No acute rejection episodes or major severe adverse events were observed in postconversion follow-up. Trend of TAC daily dose, trough level, and renal function are represented in Fig 1. Patient Adherence to Immunosuppressant Therapy
Mean VAS ratings of our patients’ adherence were already high at baseline (86%) and still increased postconversion (90%). With regard to the BAASIS, 45% of patients at baseline and 35% postconversion admitted at least one of the four abnormal behavior questioned during the previous 4 weeks. The most common behaviors were “taking” (35% at baseline and 17% postconversion) and “timing” (41% versus 32%, pre- and postconversion, respectively). No patient wished to return to twice-daily dosing. DISCUSSION
This study attempted to reproduce in a real-world setting, outside the context of a transplant center or of a controlled trial, the effectiveness of conversion from BID TAC to QD TAC in stable LT recipients. In our experience the switch on 1:1 mg basis resulted well tolerated, and tacrolimus exposure largely remained within the target range with no
CONVERSION TO ONCE-DAILY TACROLIMUS
1275
Fig 1. Mean tacrolimus daily dose (A), tacrolimus trough level (B), and estimated glomerular filtration rate (C) pre- and postconversion to once-daily tacrolimus formulation.
case of acute rejection. Approximately 70% of patients required no dose adjustment after conversion, substantially in line with another study.10 We observed a statistically significant improvement of renal function the first 6 months of conversion with a subsequent steady state. This may reflect the different pharmacokinetic profile of QD TAC with reduced nephrotoxic peak levels, despite having an equivalent exposure at steady state and trough levels.11 We also evaluated in this study nonadherence to immunosuppressive medication, a serious problem that strongly correlates with long-term outcome after liver transplantation. There are numerous data in the literature showing that the reduced frequency of dosing may help optimizing adherence.3,12,13 The use of self-assessment questionnaire, particularly the BAASIS, is increasingly recognized as a good method for assessing immunosuppressive adherence even if it isn’t the gold standard.14 PROs are defined as “outcomes reported by patients” such as symptom experience, healthrelated quality of life, and particularly medication adherence.15 Our data analysis on PROs showed a high patients’ reported adherence already with BID TAC and a not significantly higher adherence rate 6 months after conversion to QD TAC, reflecting our attention to and the patients’ good understanding of the importance of immunosuppressive therapy. Other reasons might be the high percentage of patients receiving TAC in combination with mycophenolate mofetil and the habitual behavior of patients to vary the “timing” of immunosuppressive taking, as observed in other studies.14 However, when we evaluated only the “taking,” there was a 50% reduction of nonadherent behavior, showing an improvement in adherence after conversion from QD TAC, according to other studies.3 Another aspect of this study was the involvement of the nurse, avoiding the slowdown in outpatient activity. In conclusion, the switch from BID TAC to QD TAC performed as good in real life as it did in controlled studies or in transplants centers, with the possibility to improve renal function and to increase adherence to immunosuppressant therapy. REFERENCES 1. Cholongitas E, Shusang V, Germani G, et al: Long-term follow-up of immunosuppressive monotherapy in liver transplanta-
tion: tacrolimus and microemulsified cyclosporin. Clin Transplant. 2011;25:614. 2. Marin-Gomez LM, Gomez-Bravo MA, Alamo-Martinez JA, et al: Evaluation of clinical safety of conversion to advagraf therapy in liver transplant recipients: observational study. Transplant Proc. 2009;41:2184. 3. Beckebaum S, Jacob S, Sweid D, et al: Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice-daily tacrolimus-based regimen to oncedaily tacrolimus extended-release formulation. Transpl Int. 2011; 24:666. 4. Morrissey PE, Flynn ML, Lin S: Medication noncompliance and its implications in transplant recipients. Drugs. 2007;67:1463. 5. O’Carroll RE, McGregor LM, Swanson V, et al: Adherence to medication after liver transplantation in Scotland: a pilot study. Liver Transpl. 2006;12:1862. 6. Razonable RR, Findlay JY, O’Riordan A, et al: Critical care issues in patients after liver transplantation. Liver Transpl. 2011;17:511. 7. First MR, Fitzsimmons WE: Modified release tacrolimus. Yonsei Med J. 2004;45:1127. 8. Levey AS, Bosch JP, Lwis JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease study group. Ann Intern Med. 1999;130:461. 9. De Geest S, Abraham I, Dunbar-Jacob J: Measuring transplant patients’ compliance with immunosuppressive therapy. West J Nurs Res. 1996;18:595. 10. San ´ko-Resmer J, Boillot O, Wolf P, et al: Renal function, efficacy and safety postconversion from twice- to once-daily tacrolimus in stable liver recipients: an open-label multicenter study. Transpl Int. 2012;25:283. 11. Zaltzman JS: A comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily cyclosporine on renal function in healthy volunteers. Transplantation. 2010; 90:1185. 12. Eisen SA, Miller DK, Woodward RS, et al: The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med. 1990;150:1881. 13. Weng FL, Israni AK, Joffe MM, et al: Race and electronically-measured adherence to immunosuppressive medications after deceased donor renal transplantation. J Am Soc Nephrol. 2005;16:1839. 14. Lennerling A, Forsberg A: Self-reported non-adherence and beliefs about medication in a Swedish kidney transplant population. Open Nurs J. 2012;6:41. 15. Drent G, De Geest S, Dobbels F, et al: Symptom experience, nonadherence and quality of life in adult liver transplant recipients. Neth J Med. 2009;67:161.
ABSTRACT Background. The prolonged-release once-daily (QD) tacrolimus is a formulation developed to improve adherence to immunosuppressant (IS) regimen, reducing the frequency of dosing, and to increase safety, avoiding toxic peak concentrations. We evaluated efficiency and quality of conversion from twice-daily (BID) to QD tacrolimus formulation in stable liver transplant (LT) recipients in the real-setting of a gastrohepatology team peripheral to LT centers. Patients and methods. Thirty-four LT recipients (median age 60 years, range 33– 69) were switched from BID tacrolimus to QD tacrolimus (1:1 dose) at a median of 38 months (range 8 –211) after transplantation. Tacrolimus levels and laboratory analyses were recorded before and postconversion. Adherence to IS treatment was measured by a modified “Basel Assessment of Adherence Scale to Immunosuppressives.” Results. Median postconversion follow-up was 21 months (range 6 –35, at least 12 months in 30 patients). Mean total tacrolimus daily dose and mean tacrolimus trough level were not significantly different before and after the switch (3.1 ⫾ 2.3 preconversion versus 3.1 ⫾ 2.5 and 3.0 ⫾ 2.5 mg at 6 and 12 months postconversion, respectively; and 5.3 ⫾ 1.8 preconversion versus 4.6 ⫾ 1.4 and 4.5 ⫾ 1.8 ng/mL at 6 and 12 months postconversion, respectively). All patients maintained stable liver and metabolic parameters. Renal function by glomerular filtration rate increased (67 ⫾ 17 preconversion versus 73 ⫾ 19 and 73 ⫾ 20 mL/min at 6 and 12 months postconversion, respectively; P ⫽ .003). No acute rejection episode or major severe adverse events occurred postconversion. Patientreported outcome showed a reduction of missed IS doses. Conclusion. We observed that in a real-world setting far from LT centers, the switch from BID tacrolimus to QD tacrolimus in stable LT recipients is efficient (safe and effective) to improve quality of medical care, with possibly better IS adherence and improvement of renal function. ACROLIMUS (TAC) is an immunosuppressive agent widely used to prevent allograft rejection in organ transplantation.1 An extended-release formulation of TAC has been recently developed as alternative to standard immediate-release formulation, allowing once-daily (QD) instead of twice-daily (BID) dosing, with evidence of similar safety and efficacy profiles.2,3 It is well known that nonadherence to immunosuppressant regimen, associated often to the complex and long-term treatments, results in a poor liver transplant (LT) recipient outcome.4,5 Also, renal failure is an important posttransplant cause of morbidity and mortality6 and so it is necessary to minimize the risk of
T
drug-related nephrotoxicity while maintaining a sufficient dosage to prevent rejection. Reducing the frequency of immunosuppressive dosing may improve adherence to ther-
From the UOSD Fisiopatologia Epatica con Servizio di Assistenza ai Trapiantati e Trapiantandi Epatici, AORN Sant’Anna e San Sebastiano, Caserta, Italy. Address reprint requests to Giovanna Valente, UOSD Fisiopatologia Epatica con Servizio di Assistenza ai Trapiantati e Trapiantandi Epatici, AORN Sant’Anna e San Sebastiano, Via Gennaro Tescione, 1, 81100 Caserta, Italy. E-mail: giovannavalente1977@ libero.it
© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2013.02.021
Transplantation Proceedings, 45, 1273–1275 (2013)
1273
1274
apy and at the same time may reduce the toxicity also due to BID TAC peak levels.7 In this study we evaluated effectiveness of the switch from BID to QD TAC formulation, investigating the effects of conversion on immunosuppressive adherence and renal function in stable LT recipients in the real-world setting of a gastrohepatology team peripheral to LT centers. PATIENTS AND METHODS This was an observational study conducted during the daily activities in adult LT recipients in a gastrohepatology clinic of a hospital that is not within a transplant center. The switch from BID to QD TAC regimen was based on 1:1 mg proportion and patients were converted if they had at least 8 months’ posttransplant follow-up, no acute rejection episodes in the last year, and BID TAC dose stable for at least 12 weeks prior to conversion. During follow-up, TAC doses were adjusted to maintain within the target trough concentration (3 to 6 ng/L). TAC trough levels, liver and renal function, and metabolic parameters were regularly recorded before conversion, 10 days after conversion, again on average every 2 months or whenever it was necessary. Renal function was evaluated by estimated glomerular filtration rate (eGFR) using the modified Modification of Diet in Renal Disease formula.8 Clinical evaluation, adverse events, and results of laboratory values were assessed at each visit. Patient-reported outcomes (PROs) on adherence to immunosuppressant therapy were assessed at baseline and at month 6 by a modified “Basel Assessment of Adherence to Immunosuppressive medication scale” (BAASIS Scale), consisting of a questionnaire administered to the patient in the form of interview.9 This instrument, using four items, explored “taking” (dose not taken), “skipping” (several dose repeatedly not taken), “timing” (dose taken with more than 2 hours’ delay), and “dose reduction” (without counsel of clinician), referring to the last 4 weeks. Also a visual analog scale (VAS) ranging from 0 (immunosuppressant never taken as prescribed) and 100 (always taken as prescribed) allowed patients to estimate their adherence to prescribed medication in percent. Finally, all patients expressed their preference to the once- or twice-daily regimen. The administration of the questionnaires was entrusted to our charge experienced nurse (M.S.). Informed consent was obtained from each patients.
Statistical Analysis The results are presented as mean ⫾ standard deviation or median (range) for continuous variables and percentage for categorical variables. Paired data were analyzed with a paired t test. Statistical significance was defined as a P value of less than .05. All statistical analyses were performed with Statistical Package for Social Sciences software (version 16, SPSS, Inc, Chicago, Ill, USA).
RESULTS Patients’ Characteristics at Baseline
The main baseline characteristics of liver transplant recipients are shown in Table 1 Between April 2009 and May 2011, 27 men and 7 women, median age 60 years (range 33– 69), with a posttransplantation period of a median of 38 months (range 8 –211), were switched from BID TAC to QD TAC. Immunosuppressant therapy was prevalently based on TAC in association with mycophenolate mofetil (n ⫽ 20, 59%).
VALENTE, RINALDI, SGAMBATO ET AL Table 1. Patients’ Baseline Characteristics Patients (n ⫽ 34)
Variables
Age, y (median, range) Gender (M/F) Months from transplantation (median, range) Postconversion follow-up, mo (median, range) Patients with at least 12 mo of follow-up Immunosuppression Tacrolimus monotherapy Tacrolimus ⫹ mycophenolate mofetil Tacrolimus ⫹ sirolimus Comorbidities Renal dysfunction (eGFR ⬍ 60 mL/min/1.73 m2) Diabetes mellitus Arterial hypertension Dyslipidemia
60 (33–69) 27/7 38 (8–211) 21 (6–35) 30 (88%) 13 (38%) 20 (59%) 1 (3%) 6 (17%) 5 (15%) 16 (47%) 8 (23%)
Abbreviations: eGFR, estimated glomerular filtration rate.
After the Switch to QD-TAC
Median postconversion follow-up was 21 months (range 6 –35), with at least 12 months in 30 patients. Mean TAC level (ng/mL) was 5.3 ⫾ 1.8 preconversion, with a BID dose of 3.1 ⫾ 2.3 mg. During the first 6 months, TAC dose was modified ⬎ ⫾20% of starting dose, increasing in 5/34 and decreasing in 5/34 LT recipients, in order to remain in therapeutic range. At 6 and 12 months, mean TAC levels were 4.6 ⫾ 1.4 and 4.5 ⫾ 1.8, with mean QD doses (mg) of 3.1 ⫾ 2.5 and 3.0 ⫾ 2.5, respectively. During the follow-up all patients maintained stable liver and metabolic parameters. Renal function by eGFR slightly but significantly increased (67 ⫾ 17 preconversion versus 73 ⫾ 19 and 73 ⫾ 20 mL/min at 6 and 12 months postconversion, respectively; P ⫽ .003). No acute rejection episodes or major severe adverse events were observed in postconversion follow-up. Trend of TAC daily dose, trough level, and renal function are represented in Fig 1. Patient Adherence to Immunosuppressant Therapy
Mean VAS ratings of our patients’ adherence were already high at baseline (86%) and still increased postconversion (90%). With regard to the BAASIS, 45% of patients at baseline and 35% postconversion admitted at least one of the four abnormal behavior questioned during the previous 4 weeks. The most common behaviors were “taking” (35% at baseline and 17% postconversion) and “timing” (41% versus 32%, pre- and postconversion, respectively). No patient wished to return to twice-daily dosing. DISCUSSION
This study attempted to reproduce in a real-world setting, outside the context of a transplant center or of a controlled trial, the effectiveness of conversion from BID TAC to QD TAC in stable LT recipients. In our experience the switch on 1:1 mg basis resulted well tolerated, and tacrolimus exposure largely remained within the target range with no
CONVERSION TO ONCE-DAILY TACROLIMUS
1275
Fig 1. Mean tacrolimus daily dose (A), tacrolimus trough level (B), and estimated glomerular filtration rate (C) pre- and postconversion to once-daily tacrolimus formulation.
case of acute rejection. Approximately 70% of patients required no dose adjustment after conversion, substantially in line with another study.10 We observed a statistically significant improvement of renal function the first 6 months of conversion with a subsequent steady state. This may reflect the different pharmacokinetic profile of QD TAC with reduced nephrotoxic peak levels, despite having an equivalent exposure at steady state and trough levels.11 We also evaluated in this study nonadherence to immunosuppressive medication, a serious problem that strongly correlates with long-term outcome after liver transplantation. There are numerous data in the literature showing that the reduced frequency of dosing may help optimizing adherence.3,12,13 The use of self-assessment questionnaire, particularly the BAASIS, is increasingly recognized as a good method for assessing immunosuppressive adherence even if it isn’t the gold standard.14 PROs are defined as “outcomes reported by patients” such as symptom experience, healthrelated quality of life, and particularly medication adherence.15 Our data analysis on PROs showed a high patients’ reported adherence already with BID TAC and a not significantly higher adherence rate 6 months after conversion to QD TAC, reflecting our attention to and the patients’ good understanding of the importance of immunosuppressive therapy. Other reasons might be the high percentage of patients receiving TAC in combination with mycophenolate mofetil and the habitual behavior of patients to vary the “timing” of immunosuppressive taking, as observed in other studies.14 However, when we evaluated only the “taking,” there was a 50% reduction of nonadherent behavior, showing an improvement in adherence after conversion from QD TAC, according to other studies.3 Another aspect of this study was the involvement of the nurse, avoiding the slowdown in outpatient activity. In conclusion, the switch from BID TAC to QD TAC performed as good in real life as it did in controlled studies or in transplants centers, with the possibility to improve renal function and to increase adherence to immunosuppressant therapy. REFERENCES 1. Cholongitas E, Shusang V, Germani G, et al: Long-term follow-up of immunosuppressive monotherapy in liver transplanta-
tion: tacrolimus and microemulsified cyclosporin. Clin Transplant. 2011;25:614. 2. Marin-Gomez LM, Gomez-Bravo MA, Alamo-Martinez JA, et al: Evaluation of clinical safety of conversion to advagraf therapy in liver transplant recipients: observational study. Transplant Proc. 2009;41:2184. 3. Beckebaum S, Jacob S, Sweid D, et al: Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice-daily tacrolimus-based regimen to oncedaily tacrolimus extended-release formulation. Transpl Int. 2011; 24:666. 4. Morrissey PE, Flynn ML, Lin S: Medication noncompliance and its implications in transplant recipients. Drugs. 2007;67:1463. 5. O’Carroll RE, McGregor LM, Swanson V, et al: Adherence to medication after liver transplantation in Scotland: a pilot study. Liver Transpl. 2006;12:1862. 6. Razonable RR, Findlay JY, O’Riordan A, et al: Critical care issues in patients after liver transplantation. Liver Transpl. 2011;17:511. 7. First MR, Fitzsimmons WE: Modified release tacrolimus. Yonsei Med J. 2004;45:1127. 8. Levey AS, Bosch JP, Lwis JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease study group. Ann Intern Med. 1999;130:461. 9. De Geest S, Abraham I, Dunbar-Jacob J: Measuring transplant patients’ compliance with immunosuppressive therapy. West J Nurs Res. 1996;18:595. 10. San ´ko-Resmer J, Boillot O, Wolf P, et al: Renal function, efficacy and safety postconversion from twice- to once-daily tacrolimus in stable liver recipients: an open-label multicenter study. Transpl Int. 2012;25:283. 11. Zaltzman JS: A comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily cyclosporine on renal function in healthy volunteers. Transplantation. 2010; 90:1185. 12. Eisen SA, Miller DK, Woodward RS, et al: The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med. 1990;150:1881. 13. Weng FL, Israni AK, Joffe MM, et al: Race and electronically-measured adherence to immunosuppressive medications after deceased donor renal transplantation. J Am Soc Nephrol. 2005;16:1839. 14. Lennerling A, Forsberg A: Self-reported non-adherence and beliefs about medication in a Swedish kidney transplant population. Open Nurs J. 2012;6:41. 15. Drent G, De Geest S, Dobbels F, et al: Symptom experience, nonadherence and quality of life in adult liver transplant recipients. Neth J Med. 2009;67:161.