- Email: [email protected]
Tacrolimus Effects and Side Effects After Liver Transplantation: Is There a Difference Between Immediate and Extended Release?
Tacrolimus Effects and Side Effects After Liver Transplantation: Is There a Difference Between Immediate and Extended Release? N. Weiler, I. Thrun, M. Eberlin, D. Foltys, M. Heise, M. Hoppe-Lotichius, T. Zimmermann, I. Kraemer, and G. Otto ABSTRACT Background. Immunosuppressive therapy after orthotopic liver transplantation (OLT) requires a high degree of patient compliance to guarantee safety and avoid side effects. In 2007, prolonged-release tacrolimus was launched in Europe to improve compliance. In this prospective observational crossover single-center trial, we analyzed effects and side effects of prolonged-release tacrolimus in OLT patients. Methods. LT patients at our center were included if they were older than l8 years of age, had had the procedure at least 6 months prior, and were outpatients currently on twicedaily tacrolimus. Patients were observed for 6 months before switching to once-daily tacrolimus. Patient history, clinical examination, and laboratory examinations were recorded on inclusion as well as after 3, 6, 9, 12, and 18 months. Results. The rates of rejection, hypertension, hypercholesterolemia, and diabetes mellitus were compared during twice-daily and once-daily tacrolimus. Similarly, laboratory parameters were identical during both periods with the exception of glycated hemoglobin, which was significantly elevated under once-daily tacrolimus (P ¼ .00l). Conclusion. Converting patients to extended-release tacrolimus with was safe in terms of rejection, hypertension, and hypercholesterolemia as well as renal and liver functions. Further investigations concerning pharmacokinetics and glucose metabolism will be needed to evaluate prolonged-release tacrolimus.
I
MMUNOSUPPRESSION is essential after organ transplantation to prevent rejection. Calcineurin inhibitors are usually considered to be first-line immunosuppressants in orthotopic liver transplantation (OLT). Since the early 1990s, tacrolimus has gained widespread acceptance.1,2 Apart from side effects, such as metabolic syndrome with hypertension, hyperlipidemia, diabetes, and renal insufficiency, patient compliance is a major concern in the longterm use of these drugs.3,4 Usually tacrolimus is given twice daily (twice-daily tacrolimus [TDT]). In April 2007, once-daily tacrolimus (ODT) was launched in Europe.5 There is still little information about this new formulation and its side effects. Available data have mostly focused on safety in terms of rejection among kidney transplant recipients.6,7 The rationale for the development of ODT was an improvement in compliance. Non-compliance may result in late onset of acute rejection episodes.8,9 In general, the high daily pill burden and side effects of immunosuppressive
therapy lead to noncompliance.10e12 The ideal immunosuppressant is, therefore, characterized by an uncomplicated regimen with a low pill burden, maximal safety, and minimal side effects.13 ODT may be reduce toxicity due to the lower peak of tacrolimus, but experience is limited so far.14 To elucidate these issues we performed a prospective observational crossover study using TDT followed by ODT in OLT patients, focusing on reject episodes and side effects. From the Department of Transplantation, Hepatobiliary and Pancreatic Surgery, (N.W., I.T., D.F., M.H., M.H.-L., G.O.), Medical Department I (T.Z.), Department of Pharmacy (M.E., I.K.), University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany. Address reprint requests to Nina Weiler, Department of Transplantation, Hepatobiliary and Pancreatic Surgery, Langenbeckstraße, 55131 Mainz, Germany. E-mail: nina.weiler@ unimedizin-mainz.de
ª 2013 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.03.039
Transplantation Proceedings, 45, 2321e2325 (2013)
2321
2322
PATIENTS AND METHODS Study Design and Patients This prospective observational crossover single-center trial OLT of patients was performed between August 2008 and July 2010 since 1997. Inclusion criteria were: as follows informed consent, age older than 18 years, patients at least 6 months after OLT, outpatient care at our center, and current immunosuppressive therapy with TDT. During the first year the tacrolimus trough levels immediately after OLT were targeted to 5e10 ng/mL in monotherapy and 5e8 ng/mL using other immunosuppressive drugs. Thereafter they were decreases to 3e5 ng/mL. Data were collected for 6 months during TDT treatment. Thereafter, patients were converted to ODT at an identical daily dosage as TDT. Clinical and laboratory data were collected for 6 months. Patient history, clinical examination, and laboratory examinations recorded on inclusion into the study as well as after 3, 6, 9, 12, and 18 months. The following data were obtained: serum creatinine, cholesterol, high-density lipoprotein cholesterol (HDL), lowdensity lipoprotein cholesterol (LDL), hemoglobin A1C (HbAlC), body mass index (BMI), glucose, prothrombin time, international normalized ratio, aspartate transaminase (AST), alanine transaminase (ALT), bilirubin, urea, uric acid, tacrolimus target wholeblood trough levels, creatinine clearance, proteinuria, weight, blood pressure, pulse rate, and medication regimen. Serious adverse events were recorded during the study and 6 months thereafter. They were defined as requiring hospital treatment, emergent ambulatory treatment, diseases with permanent damages, life-threatening incidents, and death. Events were classified in terms of severity, relation to tacrolimus, and consequences for the patient. Post-transplantation diabetes was defined as requiring treatment with insulin or an oral antidiabetic agent. Similarly, the requirement of treatment was the criterion for hypertension and hypercholesterolemia. Worsening renal function was diagnosed by an increased serum creatinine level or decreased creatinine clearance. All acute rejection episodes were verified using liver biopsy; if confirmed, the patients received methylprednisolon (500 mg) per day for 3 days as steroid bolus therapy. The study was performed in accordance with the declaration of Helsinki with approval of the local ethics committee.
Statistical Analysis The statistical analysis was performed in cooperation with the Institute of Medical Biometrics, Epidemiology and Informatics (IMBEI) of the Johannes Gutenberg University Mainz. Continuous normally distributed variables were analyzed using Students t test; other metric variables were investigated using the Wilcoxon signed-rank test. Categorical variables were analyzed using cross tabulations and McNemar test. Correlations between observed data were calculated using Pearson product-moment coefficient (r) for normally distributed variables and Spearman rank correlation coefficient (r) for metric but not normally distributed variables. Statistical significance was defined as P .05.
WEILER, THRUN, EBERLIN ET AL Table 1. Patient Demographics No. of patients Mean age SD (y) M:F ratio Mean duration of tacrolimus treatment SD (d) Indication for OLT* HCC Hepatitis B Hepatitis C Alcoholic cirrhosis PSC/ PBC Cryptogenic cirrhosis Morbus Wilson a1 antitrypsin deficiency Familial amyloid polyneuropathy Acute liver failure Autoimmune hepatitis Budd chiari syndrome Amanita phalloides poisoning
61 54.75 10.70 (27e77) 33:28 1424 933 (211e3683)
14 14 14 14 13 5 3 2 2 2 1 1 1
Abbreviations: M, male; F, female; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis. *Multiple assessments possible.
therefore, excluded from the analysis. One patientdalthough carefully instructeddtook the twice-daily formulation only once a day and thus was also excluded from the analysis. One patient experienced deteriorating renal function during ODT administration and wished to be converted to TDT. Three patients (5%) died during the 6 month follow-up after finishing the study. The causes of death were hepatocellular carcinoma (HCC) recurrence (n ¼ 2) or no known reason (n ¼ 1). Because their data were complete, we included them the analysis, yielding 61 evaluable patients. The demographics of these patients are shown in Table 1. Twenty-four patients (39%) received tacrolimus monotherapy. All other patients had tacrolimus combined with mycophenolate mofetil (n ¼ 26; 44%), azathioprine (n ¼ 6; 11.5%), sirolimus (n ¼ 2; 3%), or prednisolone (n ¼ 2; 3%). One patient received tacrolimus, mycophenolate mofetil, and azathioprine. Adjustment of the daily dose was required in 21 (35%) patients after the change in treatment: eleven needed dose escalation (52%), whereas 10 patients (48%) underwent dose reduction. Target whole-blood trough levels were achieved in 33 (54.1%) of the patients prescribed the twicedaily and 36 (59%) prescribed the once-daily formulation (P ¼ .678). Although the daily dose was adjusted, target whole-blood trough levels were significantly lower using the ODT tacrolimus formulation (P ¼ .000). Rejections
RESULTS
Among 437 patients who underwent transplantation in our center from 1997 until December 2007, 293 patients (67.0%) were still alive, including 189 receiving tacrohmus with three on a once-daily formulation. Of 100 patients identified to as meeting the study inclusion criteria, 65 gave their informed consent. The 2 patients who withdrew their consent were,
During the study period and follow-up, one acute rejection episodes occurred under TDT. There was no significant difference between the study phases (P ¼ 1.0). Tacrolimus Side Effects
Comparing the respective data under treatment with TDT versus ODT, there were no differences in the rates of
TACROLIMUS EFFECTS AND SIDE EFFECTS
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Table 2. Tacrolimus Side Effects Tacrolimus Immediate Release
Serum creatinine (mg/dL) Cholesterol (mg/dL) HDL (mg/dL) LDL (mg/dL) HbAlC (%) BMI (kg/m2) Glucose (mg/dL) Prothrombin time (%) INR AST (U/L) ALT (U/L) Bilirubin (mg/dL) Uric acid (mg/dL) Urea (mg/dL) Creatinine clearance (mL/min) Tacrolimus (ng/mL)
1.23 0.34 182.12 46.99 105.52 5.46 26.57 106.14 98.68 1.04 38.16 50.26 0.88 6.38 21.69 73.76
40.80 14.00 36.32 1.01 4.86 30.31 18.27 0.25 22.10 54.61 0.64 2.14 9.06 28.11
5.90 1.95
Table 4. SAE During Study Periods
Tacrolimus Extended Release
TDT P
1.22 0.37
.556
.797 .419 .302 .001 .068 .656 .146 .457 .140 .709 .913 .818 .964 .853
181.32 47.69 102.84 5.71 26.79 109.87 100.78 1.02 51.68 57.52 0.88 6.59 21.98 74.93
37.10 14.90 30.61 0.91 5.10 35.65 16.91 0.17 69.01 94.78 0.57 3.15 9.91 29.23
5.35 2.60
.000
hypertension (27 vs 27: P ¼ 1.0), diabetes mellitus (18 TDT vs 19 ODT; P ¼ 1.0) or hypercholesterolemia (8 TDT vs 9 ODT; P ¼ 1.0). We observed no significant differences in proteinuria, creatinine, cholesterol, HDL, LDL, BMI, prothrombin time, INR, AST, ALT, bilirubin, urea, uric acid, creatinine clearance, as well as glucose (Table 2). Under ODT therapy glycated HbAIC was significantly elevated compared with TDT (P ¼ .001). Based upon subgroups according to the median value before initiation of ODT, glycated hemoglobin significantly worsened under ODT therapy among patients below the medium (P ¼ .000) but remained unchanged in patients above the median (P ¼ .360). We observed a slight but significant correlation between tacrolimus whole-blood trough levels and blood glucose under therapy with TDT (P ¼ .019; r ¼ 0.299), but not ODT (P ¼ .342; r ¼ 0.125); (Table 3). In addition, the analysis demonstrated a correlation between blood glucose and glycated hemoglobin for TDT (P ¼ .000; r ¼ 0.534) and ODT (P ¼ .000; r ¼ 0.547) as well as between age and glycated hemoglobin for TDT (P ¼ .034; r ¼ 0.272) and ODT (P ¼ .007; r ¼ 0.351). No correlation could be shown between tacrolimus whole-blood trough levels and glycated hemoglobin (TDT P ¼ .3l3, r ¼ 0.131 vs ODT P ¼ .160, r ¼ 0.187) or duration of tacrolimus treatment and glycated hemoglobin (TDT P ¼ .625, r ¼ 0.064 vs ODT P ¼ .084, r ¼ 0.231).
Other Admission for routine diagnostic work-up HCC Infection Tumor Hernia Liver cirrhosis Renal insufficiency Hypertensive crisis Diabetes Rejection Unknown Weight gain Sum
ODT
Follow-Up
Sum
11 5
8 9
8 6
27 20
3 5 4 2 2 1 0 0 1 0 0 34
4 3 0 1 2 1 3 2 0 1 0 34
4 1 2 2 0 2 1 1 0 0 1 28
11 9 6 5 4 4 4 3 1 1 1 96
Serious Adverse Events
The most common serious adverse events (SAE) occurred among were “requirements for hospital treatment” (63.5%). SAE were mild (64.6%), with no probable relationship to tacrolimus (38.5%), and without permanent damage for the patient (65.6%). One SAE was classified as related to tacrolimus with clinical signs of tacrolimus intoxication during TDT. SAE recorded were admission to hospital for routine diagnostics, HCC recurrence, infection, recirrhosis, tumor, hernia, worsened hypertension, causes renal insufficiency, diabetes, weight gain, rejection, other, and unknown. Table 4 shows the occurrence of SAE under TDT and ODT as well as in follow-up under the ODT formulation. DISCUSSION
Simplification of the drug regimen is desirable as it usually results in better adherence.15e17 Adherence to critical dose drugs like tacrolimus is essential to reliably maintain target blood levels. Variability in target blood levels procedures multiple unpredictable side effects.18,19 Tacrolimus in the once-daily formulation is a new drug; and data concerning effects, especially side effects, are sparse in contrast with the twice-daily formulation. Moreover, such data have mostly been generated in kidney recipients.15,20 Florman et al have described conversion from TDT to ODT in a crossover study performed in stable adult liver transplant recipients over 56 days.21 Patients thereafter were maintained on ODT and observed for 2 years. Patient and graft survivals renal function, as well as rates of diabetes mellitus, hypertension
Table 3. Correlation Between Glucose, HbA1C, Tacrolimus, Age, and Duration of Tacrolimus Treatment Tacrolimus Immediate Release
P, r
Tacrolimus Extended Release
P, r
FK506 z Glucose Glucose z HbAlC Age z HbAlC FK 506 z HbAlC Duration of FK506 z HbAlC
P ¼ .019, r ¼ 0.299 P ¼ .000, r ¼ 0.534 P ¼ .034, r ¼ 0.272 P ¼ .313, r ¼ 0.131 P ¼ .625, r ¼ 0.064
FK506 z Glucose Glucose z HbA1C Age z HbA1C FK 506 z HbA1C Duration of FK506 z HbA1C
P ¼ .342, r ¼ 0.125 P ¼ .000, r ¼ 0.547 P ¼ .007, r ¼ 0.351 P ¼ .160, r ¼ 0.187 P ¼ .084, r ¼ 0.231
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and hyperlipidemia were recorded based on clinical judgement. Trunecka et al gave detailed information about rejection in primary liver transplant recipients enrolled in a multicenter, randomized two-arm phase 3 study.22 This study described side effects of tacrolimus in once- or twicedaily dosing considering clinical and laboratory findings. In the present study, dose adjustment after conversion to prolonged-release tacrolimus was required in one third of patients comparable with the findings of another study.23 Nevertheless, the mean whole-blood trough levels were lower under prolonged-release tacrolimus. Acute rejection episodes were equally distributed. Again, this result corroborated of the outcomes of other studies.6,24 Conversion of the drug regimen to prolonged-release tacrolimus is safe but needs dose adjustment. Hypertension, post-transplantation diabetes, hypercholesterolemia, hyperuricemia, obesity, and renal insufficiency as potential side effects of calcineurin inhibitors as well as liver function were analyzed using laboratory and clinical examinations. Between the two therapeutic regimens, there were no differences in the rates of hypertension, PTMD, hypercholesterolemia, hyperuricemia, BMI, renal function, and liver function. Although similar numbers of patients required antidiabetic therapy, glycated hemoglobin was significantly increased under ODT, especially among patients with a low glycated hemoglobin. Fasting blood glucose was not significantly different during twice versus once daily therapy. There was a correlation between fasting blood glucose and wholeblood trough levels under TDT therapy, but not under ODT. The amount of glycated hemoglobin was independent of tacrolimus whole-blood trough levels and of the duration of tacrolimus use. In kidney transplant recipients Alloway et al observed no significant differences in tacrolimus side effects using immediate-versus prolonged-release formulations.7 Our results indicated that fasting blood glucose was not exclusively causative for elevated glycated hemoglobin values presumption of during ODT. Because the area under the curve was similar regardless of whether tacrolimus immediate- or extended-release was administered, we hypothesize that elevated glycated hemoglobin may be controlled by the daily blood sugar profile that not by the fasting glucose.6,20,21 The lack of correlation of high blood trough tacrolimus levels and glycated hemoglobin deserves further investigation. This prospective observational crossover single-center study observed significant, alter weak, correlations between tacrolimus, glucose, and glycated hemoglobin. Therefore, we recommend a randomized trial to dissect glucose metabolism under immediate, and prolonged-release tacrolimus. Only a little information is available on the impact of pharmacokinetics on therapentin versus side effects, particularly for drugs in prolonged-release formulation. These issues are being pursued by various studies. The ODT formulation seems to improve adherence in transplant recipients.25 However, any change in immunosuppression requires careful consideration. This study showed that conversion of liver transplant recipients from tacrolimus
WEILER, THRUN, EBERLIN ET AL
with immediate to prolonged release was safe, often needing dose adjustments, and should be carefully reconsidered among patients an impaired glucose tolerance. REFERENCES 1. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet. 1989;2:1000e1004. 2. Todo S, Fung JJ, Starzl TE, et al. Liver, kidney, and thoracic organ transplantation under FK 506. Ann Surg. 1990;212:295e305; discussion 6e7. 3. Starzl TE, Abu-Elmagd K, Tzakis A, Fung JJ, Porter KA, Todo S. Selected topics on FK 506, with special references to rescue of extrahepatic whole organ grafts, transplantation of “forbidden organs,” side effects, mechanisms, and practical pharmacokinetics. Transplant Proc. 1991;23:914e919. 4. European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Lancet. 1994;344:423e428. 5. First MR. First clinical experience with the new once-daily formulation of tacrolimus. Ther Drug Monit. 2008;30:159e166. 6. Heffron TG, Pescovitz MD, Florman S, et al. Once-daily tacrolimus extended-release formulation: 1-year post-conversion in stable pediatric liver transplant recipients. Am J Transplant. 2007;7: 1609e1615. 7. Alloway R, Steinberg S, Khalil K, et al. Two years postconversion from a prograf-based regimen to a once-daily tacrolimus extended-release formulation in stable kidney transplant recipients. Transplantation. 2007;83:1648e1651. 8. Mor E, Gonwa TA, Husberg BS, Goldstein RM, Klintmalm GB. Late-onset acute rejection in orthotopic liver transplantationeassociated risk factors and outcome. Transplantation. 1992;54:821e824. 9. Germani G, Lazzaro S, Gnoato F, et al. Nonadherent behaviors after solid organ transplantation. Transplant Proc. 2011;43:318e323. 10. Juday T, Gupta S, Grimm K, Wagner S, Kim E. Factors associated with complete adherence to HIV combination antiretroviral therapy. HIV Clin Trials. 2011;12:71e78. 11. Lakatos PL. Use of new once-daily 5-aminosalicylic acid preparations in the treatment of ulcerative colitis: is there anything new under the sun? World J Gastroenterol. 2009;l5:1799e1804. 12. Burra P, Germani G, Gnoato F, et al. Adherence in liver transplant recipients. Liver Transpl. 2011;17(7):760e770. 13. Yabu JM, Vincenti F. Kidney transplantation: the ideal immunosuppression regimen. Adv Chronic Kidney Dis. 2009;16:226e233. 14. van Hooff JP, Alloway RR, Trunecka P, Mourad M. Fouryear experience with tacrolimus once-daily prolonged release in patients from phase II conversion and de novo kidney, liver, and heart studies. Clin Transplant. 2011;25:EleE12. 15. Jabbour S, Ziring B. Advantages of extended-release metformin in patients with type 2 diabetes mellitus. Postgrad Med. 2011;123:15e23. 16. Oliveira L, Cohen RD. Maintaining remission in ulcerative colitis - role of once daily extended-release mesalamine. Drug Des Devel Ther. 2011;5:111e116. 17. Hansen R, Seifeldin R, Noe L. Medication adherence in chronic disease: issues in posttransplant immunosuppression. Transplant Proc. 2007;39:1287e1300. 18. Hartmann B, Schmid G, Graeb C, et al. Biochemical monitoring of mTOR inhibitor- based immunosuppression following kidney transplantation: a novel approach for tailored immunosuppressive therapy. Kidney Int. 2005;68:2593e2598. 19. Pollock-Barziv SM, Finkelstein Y, Manlhiot C, et al. Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children. Pediatr Transplant. 2010;14:968e975.
TACROLIMUS EFFECTS AND SIDE EFFECTS 20. Alloway R, Steinberg S, Khalil K, et al. Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc. 2005;37:867e870. 21. Florman S, Alloway R, Kalayoglu M, et al. Conversion of stable liver transplant recipients from a twice-daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc. 2005;37:1211e1213. 22. Trunecka P, Boillot O, Seehofer D, et al. Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation. Am J Transplant. 2010;10:2313e2322.
2325 23. Merli M, Di Menna S, Giusto M, et al. Conversion from twice-daily to once-daily tacrolimus administration in liver transplant patient. Transplant Proc. 2010;42:1322e1374. 24. Florman S, Alloway R, Kalayoglu M, et al. Once-daily tacrolimus extended release formulation: experience at 2 years postconversion from Prograf-based regimen in stable liver transplant recipients. Transplantation. 2007;83:1639e1642. 25. Doesch AO, Mueller S, Konstandin M, et al. Increased adherence after switch from twice daily calcineurin inhibitor based treatment to once daily modified released tacrolimus in heart transplantation: a pre-experimental study. Transplant Proc. 2010;42: 4238e4242.
I
MMUNOSUPPRESSION is essential after organ transplantation to prevent rejection. Calcineurin inhibitors are usually considered to be first-line immunosuppressants in orthotopic liver transplantation (OLT). Since the early 1990s, tacrolimus has gained widespread acceptance.1,2 Apart from side effects, such as metabolic syndrome with hypertension, hyperlipidemia, diabetes, and renal insufficiency, patient compliance is a major concern in the longterm use of these drugs.3,4 Usually tacrolimus is given twice daily (twice-daily tacrolimus [TDT]). In April 2007, once-daily tacrolimus (ODT) was launched in Europe.5 There is still little information about this new formulation and its side effects. Available data have mostly focused on safety in terms of rejection among kidney transplant recipients.6,7 The rationale for the development of ODT was an improvement in compliance. Non-compliance may result in late onset of acute rejection episodes.8,9 In general, the high daily pill burden and side effects of immunosuppressive
therapy lead to noncompliance.10e12 The ideal immunosuppressant is, therefore, characterized by an uncomplicated regimen with a low pill burden, maximal safety, and minimal side effects.13 ODT may be reduce toxicity due to the lower peak of tacrolimus, but experience is limited so far.14 To elucidate these issues we performed a prospective observational crossover study using TDT followed by ODT in OLT patients, focusing on reject episodes and side effects. From the Department of Transplantation, Hepatobiliary and Pancreatic Surgery, (N.W., I.T., D.F., M.H., M.H.-L., G.O.), Medical Department I (T.Z.), Department of Pharmacy (M.E., I.K.), University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany. Address reprint requests to Nina Weiler, Department of Transplantation, Hepatobiliary and Pancreatic Surgery, Langenbeckstraße, 55131 Mainz, Germany. E-mail: nina.weiler@ unimedizin-mainz.de
ª 2013 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.03.039
Transplantation Proceedings, 45, 2321e2325 (2013)
2321
2322
PATIENTS AND METHODS Study Design and Patients This prospective observational crossover single-center trial OLT of patients was performed between August 2008 and July 2010 since 1997. Inclusion criteria were: as follows informed consent, age older than 18 years, patients at least 6 months after OLT, outpatient care at our center, and current immunosuppressive therapy with TDT. During the first year the tacrolimus trough levels immediately after OLT were targeted to 5e10 ng/mL in monotherapy and 5e8 ng/mL using other immunosuppressive drugs. Thereafter they were decreases to 3e5 ng/mL. Data were collected for 6 months during TDT treatment. Thereafter, patients were converted to ODT at an identical daily dosage as TDT. Clinical and laboratory data were collected for 6 months. Patient history, clinical examination, and laboratory examinations recorded on inclusion into the study as well as after 3, 6, 9, 12, and 18 months. The following data were obtained: serum creatinine, cholesterol, high-density lipoprotein cholesterol (HDL), lowdensity lipoprotein cholesterol (LDL), hemoglobin A1C (HbAlC), body mass index (BMI), glucose, prothrombin time, international normalized ratio, aspartate transaminase (AST), alanine transaminase (ALT), bilirubin, urea, uric acid, tacrolimus target wholeblood trough levels, creatinine clearance, proteinuria, weight, blood pressure, pulse rate, and medication regimen. Serious adverse events were recorded during the study and 6 months thereafter. They were defined as requiring hospital treatment, emergent ambulatory treatment, diseases with permanent damages, life-threatening incidents, and death. Events were classified in terms of severity, relation to tacrolimus, and consequences for the patient. Post-transplantation diabetes was defined as requiring treatment with insulin or an oral antidiabetic agent. Similarly, the requirement of treatment was the criterion for hypertension and hypercholesterolemia. Worsening renal function was diagnosed by an increased serum creatinine level or decreased creatinine clearance. All acute rejection episodes were verified using liver biopsy; if confirmed, the patients received methylprednisolon (500 mg) per day for 3 days as steroid bolus therapy. The study was performed in accordance with the declaration of Helsinki with approval of the local ethics committee.
Statistical Analysis The statistical analysis was performed in cooperation with the Institute of Medical Biometrics, Epidemiology and Informatics (IMBEI) of the Johannes Gutenberg University Mainz. Continuous normally distributed variables were analyzed using Students t test; other metric variables were investigated using the Wilcoxon signed-rank test. Categorical variables were analyzed using cross tabulations and McNemar test. Correlations between observed data were calculated using Pearson product-moment coefficient (r) for normally distributed variables and Spearman rank correlation coefficient (r) for metric but not normally distributed variables. Statistical significance was defined as P .05.
WEILER, THRUN, EBERLIN ET AL Table 1. Patient Demographics No. of patients Mean age SD (y) M:F ratio Mean duration of tacrolimus treatment SD (d) Indication for OLT* HCC Hepatitis B Hepatitis C Alcoholic cirrhosis PSC/ PBC Cryptogenic cirrhosis Morbus Wilson a1 antitrypsin deficiency Familial amyloid polyneuropathy Acute liver failure Autoimmune hepatitis Budd chiari syndrome Amanita phalloides poisoning
61 54.75 10.70 (27e77) 33:28 1424 933 (211e3683)
14 14 14 14 13 5 3 2 2 2 1 1 1
Abbreviations: M, male; F, female; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis. *Multiple assessments possible.
therefore, excluded from the analysis. One patientdalthough carefully instructeddtook the twice-daily formulation only once a day and thus was also excluded from the analysis. One patient experienced deteriorating renal function during ODT administration and wished to be converted to TDT. Three patients (5%) died during the 6 month follow-up after finishing the study. The causes of death were hepatocellular carcinoma (HCC) recurrence (n ¼ 2) or no known reason (n ¼ 1). Because their data were complete, we included them the analysis, yielding 61 evaluable patients. The demographics of these patients are shown in Table 1. Twenty-four patients (39%) received tacrolimus monotherapy. All other patients had tacrolimus combined with mycophenolate mofetil (n ¼ 26; 44%), azathioprine (n ¼ 6; 11.5%), sirolimus (n ¼ 2; 3%), or prednisolone (n ¼ 2; 3%). One patient received tacrolimus, mycophenolate mofetil, and azathioprine. Adjustment of the daily dose was required in 21 (35%) patients after the change in treatment: eleven needed dose escalation (52%), whereas 10 patients (48%) underwent dose reduction. Target whole-blood trough levels were achieved in 33 (54.1%) of the patients prescribed the twicedaily and 36 (59%) prescribed the once-daily formulation (P ¼ .678). Although the daily dose was adjusted, target whole-blood trough levels were significantly lower using the ODT tacrolimus formulation (P ¼ .000). Rejections
RESULTS
Among 437 patients who underwent transplantation in our center from 1997 until December 2007, 293 patients (67.0%) were still alive, including 189 receiving tacrohmus with three on a once-daily formulation. Of 100 patients identified to as meeting the study inclusion criteria, 65 gave their informed consent. The 2 patients who withdrew their consent were,
During the study period and follow-up, one acute rejection episodes occurred under TDT. There was no significant difference between the study phases (P ¼ 1.0). Tacrolimus Side Effects
Comparing the respective data under treatment with TDT versus ODT, there were no differences in the rates of
TACROLIMUS EFFECTS AND SIDE EFFECTS
2323
Table 2. Tacrolimus Side Effects Tacrolimus Immediate Release
Serum creatinine (mg/dL) Cholesterol (mg/dL) HDL (mg/dL) LDL (mg/dL) HbAlC (%) BMI (kg/m2) Glucose (mg/dL) Prothrombin time (%) INR AST (U/L) ALT (U/L) Bilirubin (mg/dL) Uric acid (mg/dL) Urea (mg/dL) Creatinine clearance (mL/min) Tacrolimus (ng/mL)
1.23 0.34 182.12 46.99 105.52 5.46 26.57 106.14 98.68 1.04 38.16 50.26 0.88 6.38 21.69 73.76
40.80 14.00 36.32 1.01 4.86 30.31 18.27 0.25 22.10 54.61 0.64 2.14 9.06 28.11
5.90 1.95
Table 4. SAE During Study Periods
Tacrolimus Extended Release
TDT P
1.22 0.37
.556
.797 .419 .302 .001 .068 .656 .146 .457 .140 .709 .913 .818 .964 .853
181.32 47.69 102.84 5.71 26.79 109.87 100.78 1.02 51.68 57.52 0.88 6.59 21.98 74.93
37.10 14.90 30.61 0.91 5.10 35.65 16.91 0.17 69.01 94.78 0.57 3.15 9.91 29.23
5.35 2.60
.000
hypertension (27 vs 27: P ¼ 1.0), diabetes mellitus (18 TDT vs 19 ODT; P ¼ 1.0) or hypercholesterolemia (8 TDT vs 9 ODT; P ¼ 1.0). We observed no significant differences in proteinuria, creatinine, cholesterol, HDL, LDL, BMI, prothrombin time, INR, AST, ALT, bilirubin, urea, uric acid, creatinine clearance, as well as glucose (Table 2). Under ODT therapy glycated HbAIC was significantly elevated compared with TDT (P ¼ .001). Based upon subgroups according to the median value before initiation of ODT, glycated hemoglobin significantly worsened under ODT therapy among patients below the medium (P ¼ .000) but remained unchanged in patients above the median (P ¼ .360). We observed a slight but significant correlation between tacrolimus whole-blood trough levels and blood glucose under therapy with TDT (P ¼ .019; r ¼ 0.299), but not ODT (P ¼ .342; r ¼ 0.125); (Table 3). In addition, the analysis demonstrated a correlation between blood glucose and glycated hemoglobin for TDT (P ¼ .000; r ¼ 0.534) and ODT (P ¼ .000; r ¼ 0.547) as well as between age and glycated hemoglobin for TDT (P ¼ .034; r ¼ 0.272) and ODT (P ¼ .007; r ¼ 0.351). No correlation could be shown between tacrolimus whole-blood trough levels and glycated hemoglobin (TDT P ¼ .3l3, r ¼ 0.131 vs ODT P ¼ .160, r ¼ 0.187) or duration of tacrolimus treatment and glycated hemoglobin (TDT P ¼ .625, r ¼ 0.064 vs ODT P ¼ .084, r ¼ 0.231).
Other Admission for routine diagnostic work-up HCC Infection Tumor Hernia Liver cirrhosis Renal insufficiency Hypertensive crisis Diabetes Rejection Unknown Weight gain Sum
ODT
Follow-Up
Sum
11 5
8 9
8 6
27 20
3 5 4 2 2 1 0 0 1 0 0 34
4 3 0 1 2 1 3 2 0 1 0 34
4 1 2 2 0 2 1 1 0 0 1 28
11 9 6 5 4 4 4 3 1 1 1 96
Serious Adverse Events
The most common serious adverse events (SAE) occurred among were “requirements for hospital treatment” (63.5%). SAE were mild (64.6%), with no probable relationship to tacrolimus (38.5%), and without permanent damage for the patient (65.6%). One SAE was classified as related to tacrolimus with clinical signs of tacrolimus intoxication during TDT. SAE recorded were admission to hospital for routine diagnostics, HCC recurrence, infection, recirrhosis, tumor, hernia, worsened hypertension, causes renal insufficiency, diabetes, weight gain, rejection, other, and unknown. Table 4 shows the occurrence of SAE under TDT and ODT as well as in follow-up under the ODT formulation. DISCUSSION
Simplification of the drug regimen is desirable as it usually results in better adherence.15e17 Adherence to critical dose drugs like tacrolimus is essential to reliably maintain target blood levels. Variability in target blood levels procedures multiple unpredictable side effects.18,19 Tacrolimus in the once-daily formulation is a new drug; and data concerning effects, especially side effects, are sparse in contrast with the twice-daily formulation. Moreover, such data have mostly been generated in kidney recipients.15,20 Florman et al have described conversion from TDT to ODT in a crossover study performed in stable adult liver transplant recipients over 56 days.21 Patients thereafter were maintained on ODT and observed for 2 years. Patient and graft survivals renal function, as well as rates of diabetes mellitus, hypertension
Table 3. Correlation Between Glucose, HbA1C, Tacrolimus, Age, and Duration of Tacrolimus Treatment Tacrolimus Immediate Release
P, r
Tacrolimus Extended Release
P, r
FK506 z Glucose Glucose z HbAlC Age z HbAlC FK 506 z HbAlC Duration of FK506 z HbAlC
P ¼ .019, r ¼ 0.299 P ¼ .000, r ¼ 0.534 P ¼ .034, r ¼ 0.272 P ¼ .313, r ¼ 0.131 P ¼ .625, r ¼ 0.064
FK506 z Glucose Glucose z HbA1C Age z HbA1C FK 506 z HbA1C Duration of FK506 z HbA1C
P ¼ .342, r ¼ 0.125 P ¼ .000, r ¼ 0.547 P ¼ .007, r ¼ 0.351 P ¼ .160, r ¼ 0.187 P ¼ .084, r ¼ 0.231
2324
and hyperlipidemia were recorded based on clinical judgement. Trunecka et al gave detailed information about rejection in primary liver transplant recipients enrolled in a multicenter, randomized two-arm phase 3 study.22 This study described side effects of tacrolimus in once- or twicedaily dosing considering clinical and laboratory findings. In the present study, dose adjustment after conversion to prolonged-release tacrolimus was required in one third of patients comparable with the findings of another study.23 Nevertheless, the mean whole-blood trough levels were lower under prolonged-release tacrolimus. Acute rejection episodes were equally distributed. Again, this result corroborated of the outcomes of other studies.6,24 Conversion of the drug regimen to prolonged-release tacrolimus is safe but needs dose adjustment. Hypertension, post-transplantation diabetes, hypercholesterolemia, hyperuricemia, obesity, and renal insufficiency as potential side effects of calcineurin inhibitors as well as liver function were analyzed using laboratory and clinical examinations. Between the two therapeutic regimens, there were no differences in the rates of hypertension, PTMD, hypercholesterolemia, hyperuricemia, BMI, renal function, and liver function. Although similar numbers of patients required antidiabetic therapy, glycated hemoglobin was significantly increased under ODT, especially among patients with a low glycated hemoglobin. Fasting blood glucose was not significantly different during twice versus once daily therapy. There was a correlation between fasting blood glucose and wholeblood trough levels under TDT therapy, but not under ODT. The amount of glycated hemoglobin was independent of tacrolimus whole-blood trough levels and of the duration of tacrolimus use. In kidney transplant recipients Alloway et al observed no significant differences in tacrolimus side effects using immediate-versus prolonged-release formulations.7 Our results indicated that fasting blood glucose was not exclusively causative for elevated glycated hemoglobin values presumption of during ODT. Because the area under the curve was similar regardless of whether tacrolimus immediate- or extended-release was administered, we hypothesize that elevated glycated hemoglobin may be controlled by the daily blood sugar profile that not by the fasting glucose.6,20,21 The lack of correlation of high blood trough tacrolimus levels and glycated hemoglobin deserves further investigation. This prospective observational crossover single-center study observed significant, alter weak, correlations between tacrolimus, glucose, and glycated hemoglobin. Therefore, we recommend a randomized trial to dissect glucose metabolism under immediate, and prolonged-release tacrolimus. Only a little information is available on the impact of pharmacokinetics on therapentin versus side effects, particularly for drugs in prolonged-release formulation. These issues are being pursued by various studies. The ODT formulation seems to improve adherence in transplant recipients.25 However, any change in immunosuppression requires careful consideration. This study showed that conversion of liver transplant recipients from tacrolimus
WEILER, THRUN, EBERLIN ET AL
with immediate to prolonged release was safe, often needing dose adjustments, and should be carefully reconsidered among patients an impaired glucose tolerance. REFERENCES 1. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet. 1989;2:1000e1004. 2. Todo S, Fung JJ, Starzl TE, et al. Liver, kidney, and thoracic organ transplantation under FK 506. Ann Surg. 1990;212:295e305; discussion 6e7. 3. Starzl TE, Abu-Elmagd K, Tzakis A, Fung JJ, Porter KA, Todo S. Selected topics on FK 506, with special references to rescue of extrahepatic whole organ grafts, transplantation of “forbidden organs,” side effects, mechanisms, and practical pharmacokinetics. Transplant Proc. 1991;23:914e919. 4. European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Lancet. 1994;344:423e428. 5. First MR. First clinical experience with the new once-daily formulation of tacrolimus. Ther Drug Monit. 2008;30:159e166. 6. Heffron TG, Pescovitz MD, Florman S, et al. Once-daily tacrolimus extended-release formulation: 1-year post-conversion in stable pediatric liver transplant recipients. Am J Transplant. 2007;7: 1609e1615. 7. Alloway R, Steinberg S, Khalil K, et al. Two years postconversion from a prograf-based regimen to a once-daily tacrolimus extended-release formulation in stable kidney transplant recipients. Transplantation. 2007;83:1648e1651. 8. Mor E, Gonwa TA, Husberg BS, Goldstein RM, Klintmalm GB. Late-onset acute rejection in orthotopic liver transplantationeassociated risk factors and outcome. Transplantation. 1992;54:821e824. 9. Germani G, Lazzaro S, Gnoato F, et al. Nonadherent behaviors after solid organ transplantation. Transplant Proc. 2011;43:318e323. 10. Juday T, Gupta S, Grimm K, Wagner S, Kim E. Factors associated with complete adherence to HIV combination antiretroviral therapy. HIV Clin Trials. 2011;12:71e78. 11. Lakatos PL. Use of new once-daily 5-aminosalicylic acid preparations in the treatment of ulcerative colitis: is there anything new under the sun? World J Gastroenterol. 2009;l5:1799e1804. 12. Burra P, Germani G, Gnoato F, et al. Adherence in liver transplant recipients. Liver Transpl. 2011;17(7):760e770. 13. Yabu JM, Vincenti F. Kidney transplantation: the ideal immunosuppression regimen. Adv Chronic Kidney Dis. 2009;16:226e233. 14. van Hooff JP, Alloway RR, Trunecka P, Mourad M. Fouryear experience with tacrolimus once-daily prolonged release in patients from phase II conversion and de novo kidney, liver, and heart studies. Clin Transplant. 2011;25:EleE12. 15. Jabbour S, Ziring B. Advantages of extended-release metformin in patients with type 2 diabetes mellitus. Postgrad Med. 2011;123:15e23. 16. Oliveira L, Cohen RD. Maintaining remission in ulcerative colitis - role of once daily extended-release mesalamine. Drug Des Devel Ther. 2011;5:111e116. 17. Hansen R, Seifeldin R, Noe L. Medication adherence in chronic disease: issues in posttransplant immunosuppression. Transplant Proc. 2007;39:1287e1300. 18. Hartmann B, Schmid G, Graeb C, et al. Biochemical monitoring of mTOR inhibitor- based immunosuppression following kidney transplantation: a novel approach for tailored immunosuppressive therapy. Kidney Int. 2005;68:2593e2598. 19. Pollock-Barziv SM, Finkelstein Y, Manlhiot C, et al. Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children. Pediatr Transplant. 2010;14:968e975.
TACROLIMUS EFFECTS AND SIDE EFFECTS 20. Alloway R, Steinberg S, Khalil K, et al. Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc. 2005;37:867e870. 21. Florman S, Alloway R, Kalayoglu M, et al. Conversion of stable liver transplant recipients from a twice-daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc. 2005;37:1211e1213. 22. Trunecka P, Boillot O, Seehofer D, et al. Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation. Am J Transplant. 2010;10:2313e2322.
2325 23. Merli M, Di Menna S, Giusto M, et al. Conversion from twice-daily to once-daily tacrolimus administration in liver transplant patient. Transplant Proc. 2010;42:1322e1374. 24. Florman S, Alloway R, Kalayoglu M, et al. Once-daily tacrolimus extended release formulation: experience at 2 years postconversion from Prograf-based regimen in stable liver transplant recipients. Transplantation. 2007;83:1639e1642. 25. Doesch AO, Mueller S, Konstandin M, et al. Increased adherence after switch from twice daily calcineurin inhibitor based treatment to once daily modified released tacrolimus in heart transplantation: a pre-experimental study. Transplant Proc. 2010;42: 4238e4242.