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Conversion of Heart Transplant Patients From Standard to Sustained-Release Tacrolimus Requires a Dosage Increase
Conversion of Heart Transplant Patients From Standard to Sustained-Release Tacrolimus Requires a Dosage Increase R. Marzoa-Rivas, M.J. Paniagua-Martín, E. Barge-Caballero, V. Pedrosa del Moral, G. Barge-Caballero, Z. Grille-Cancela, C. Naya-Leira, P. Fariñas-Garrido, P. Blanco-Canosa, V. Mosquera, A. Castro-Beiras, and M.G. Crespo-Leiro ABSTRACT Introduction. It has been suggested that for adequate maintenance of tacrolimus levels, the total daily dosage should be increased when switching from the conventional twice-daily regimen tacrolimus (CT) to once-daily sustained-release tacrolimus (SR-T). Objective. To evaluate the safety and efficacy of a 25% increase in daily dosage when switching heart transplant (HT) patients from CT to SR-T. Methods. We switched 75 HT patients including 72% males and an overall mean age of 55.6 years from CT to SR-T using a 25% increase in daily dosage. We screened for adverse events by measurements of lipids, creatinine, glycemia, and tacrolimus in blood samples taken at 1, 3, 7, and 12 weeks after the conversion, as well as by repeated echocardiography and routine clinical examinations. Results. Just two patients (2.7%) were returned to CT because of failure of SR-T to attain therapeutic levels. In the remainder of subjects, tacrolimus levels remained stable, with trough values of 8.7 ⫾ 3.2, 8.7 ⫾ 2.9, 8.3 ⫾ 2.6, and 7.5 ⫾ 2.0 mg/dL, respectively. Twenty-three patients (31%) required no dosage change in the first 3 months, but 44 (33%) required one or two changes. No departure from therapeutic levels was associated with rejection; there was no case of severe intercurrent infection. We did not observe significant changes in glycemia, creatinine, lipid profile, or blood pressure. Conclusions. Administration of SR-T at a dosage 25% higher than the daily dosage of CT was safe. It ensured adequate tacrolimus levels in one-third of patients. Nevertheless, strict analytical surveillance is necessary during the initial months to allow dosage adjustments and to detect the minority of patients for whom SR-T does not achieve therapeutic tacrolimus levels. HE MULTIPLICITY OF DRUGS taken daily by solid organ transplant patients may provide a motive for noncompliance to the therapeutic regimen.1,2 In the case of tacrolimus, the standard regimen of conventional tacrolimus (CT), one dose every 12 hours, can now be replaced by a single daily dose of sustained release tacrolimus (SR-T). However, due to the different pharmacokinetic properties of the two dosage forms, there is some uncertainty about what dosage of SR-T is really equivalent, in therapeutic terms, to a given daily dosage of CT. Data from pharmacokinetic phase II trials have suggested that conversion on a milligram-for-milligram basis affords steady-state systemic exposure to tacrolimus
T
that is within the limits of equivalence albeit 5% to 10% lower than that achieved with CT.3 However, few studies have involved heart transplant (HT) patients. Among primary orthotopic HT patients treated with SR-T,
From the Advanced Heart Failure and Heart Transplant Unit, Hospital Universitario A Coruña, A Coruña, Spain. Financial support of this research was provided by Spanish Ministry of Health and Consumer Affairs through the Carlos III Institute Cardiovascular Research Network RECAVA. Address reprint requests to Raquel Marzoa Rivas, Hospital Universitario A Coruña, Xubias 84, 15006 La Coruña, Spain. E-mail: [email protected]
0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.08.020
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2994
Transplantation Proceedings, 42, 2994 –2996 (2010)
SUSTAINED-RELEASE TACROLIMUS
smaller areas under the tacrolimus concentration-time curve have been associated with an increased rejection rate.3 Herein, we have reported the results of a retrospective analysis of the safety and efficacy of switching stable HT patients from CT to a 25% larger daily dosage of SR-T. METHODS Conversion Protocol For a patient taking a daily dose d of CT, SR-T was introduced at a daily dose of 1.25 ⫻ d. In addition to routine HT follow-up examinations, blood samples obtained at 1, 3, 7, and 12 weeks after the switch were analyzed for creatinine, glucose, tacrolimus and lipids—low-density lipoprotein, high-density lipoprotein, total cholesterol, and triglycerides. Echocardiograms were obtained every 3 or 4 months, or when there was a suspicion of allograft dysfunction.
Study Design We examined the records of all HT patients attending our center who had been converted from CT to SR-T at least 3 months prior to the study date. The variables included the CT dosage at the time of the switch; the number of dosage changes in the first 3 months after the switch to SR-T; whether and why SR-T had been suspended; graft performance; blood analysis results; blood pressures changes in antihypertensive or hypolipidemic therapy; and adverse events. The therapeutic range for tacrolimus levels was considered to be 10 to 15 ng/mL within the first year after HT, and 5 to 15 ng/mL thereafter.
Statistical Analyses Results are reported as mean values ⫾ standard deviations or as percentages, as appropriate. Between-group differences in the former were evaluated by means of Student t test. The criterion for statistical significance was P ⬍ .05. All statistical calculations were performed using SPSS 16.0.
RESULTS
The criteria for inclusion in the study were satisfied by 75 HT patients including 72% males. The switch from CT to SR-T took place at 61.7 ⫾ 48.5 months after HT; the mean patient age was 55.6 years. Postswitch follow-up was 15.7 ⫾ 4.0 months. The CT dosage at the time of the switch was 3.7 ⫾ 2.3 mg daily. Two patients (2.7%) returned to CT within 3 months of intensive surveillance because of failure of SR-T to attain therapeutic levels despite successive dosage increases. Among the other 73 patients, tacrolimus levels remained stable, with values of 8.7 ⫾ 3.2, 8.7 ⫾ 2.9, 8.3 ⫾ 2.6, and 7.5 ⫾ 2.0 mg/dL at 1, 3, 7, and 12 weeks, respectively. Twenty-three patients (31%) required no tacrolimus dosage change in the first 3 months, and another 44 (33%) required only one or two changes. In 51 patients (68%), tacrolimus levels remained within the therapeutic range throughout the 3 months, with one exception among another 11 (15%). Glycemia, creatinine, lipids, and blood pressures measured 3 months postswitch did not differ significantly from
2995
preswitch values. No patient required a change in antihypertensive or hypolipidemic therapy during this period; no echocardiographic signs of graft dysfunction were observed; and there were no cases of severe intercurrent infection. On days 9, 42, and 43 postswitch, three patients (4%) provided endomyocardial biopsy specimens compatible with cellular rejection (International Society of Heart and Lung Transplantation grade 2R in two cases and grade 1R in one), but none of them exhibited hemodynamic instability or ventricular dysfunction during the rejection episode. Subtherapeutic tacrolimus levels were not observed either before or during these episodes. The pre-episode SR-T regimen was maintained during or after the episode in all three cases. DISCUSSION
Little has been published on the use of SR-T for HT patients. In particular, there have been no sizeable randomized studies to evaluate whether and by what amount the daily tacrolimus dosage needs to be changed when switching from CT to SR-T. Our results showed that, with appropriate surveillance measures, switching a 25% larger dosage of SR-T than CT maintained both safety and efficacy, avoiding both excessive and deficient immunosuppression. Among kidney and liver transplant patients on a CT regimen, some authors4 –7 have used the same initial daily dosage of SR-T, although tacrolimus trough levels fell and in many cases subjects required dose adjustment. In de novo kidney transplant patients, SR-T has initially afforded a smaller area under tacrolimus concentration-time curves. In some cases, a 50% higher dosage had to be used to achieve adequate levels, at least during the first month after the switch from CT.8,9 The switching protocol employed in our center sought to maintain therapeutic tacrolimus levels while avoiding overimmunosuppression. No cases of rejection episodes were associated with low tacrolimus concentrations. In two patients, SR-T failed to achieve therapeutic tacrolimus levels. The causes of these failures are unknown, but they may have involved alterations in intestinal absorption and/or unfavorable cytochrome P4503A polymorphisms.9,10 In conclusion, switching from CT to a 25% larger daily dosage of SR-T was safe. For one-third of patients, it was associated with adequate tacrolimus levels without further dosage adjustment. Nevertheless, strict analytical surveillance is necessary during the initial months so as to allow dosage adjustments for the remaining two-thirds of patients and to detect the small minority of cases among whom SR-T fails to achieve therapeutic tacrolimus levels. REFERENCES 1. Pinsky BW, Takemoto SK, Lentine KL, et al: Transplant outcomes and economic costs associated with patient noncompliance to immunosuppression. Am J Transplant 9:2597, 2009 2. O’Grady JG, Asderakis A, Bradley R, et al: Multidisciplinary insights into optimizing adherence after solid organ transplantation. Transplantation 89:627, 2010 3. Australian Therapeutic Goods Administration: Australian public assessment report for tacrolimus. Department of Health and
2996 Ageing, May 2010. Available at: www.tga.gov.au/pmeds/auspar/ auspar-prograf-xl.pdf. Accessed June 11, 2010 4. Gallego-Valcarce E, Ortega-Cerrato A, Llamas-Fuentes F, et al: Conversion to tacrolimus extendedrelease formulation: shortterm clinical results. Transplant Proc 41:2326, 2009 5. Diez Ojea B, Alonso Alvarez M, Aguado Fernández S, et al: Three-month experience with tacrolimus once-daily regimen in stable renal allografts. Transplant Proc 41:2323, 2009 6. First MR: First clinical experience with the new once-daily formulation of tacrolimus. Ther Drug Monit 30:159, 2008 7. Marin-Gomez LM, Gomez-Bravo MA, Alamo-Martinez JA, et al: Evaluation of clinical safety of conversion to Advagraf
MARZOA-RIVAS, PANIAGUA-MARTÍN, BARGE-CABALLERO ET AL therapy in liver transplant recipients: observational study. Transplant Proc 41:2184, 2009 8. Wlodarczyk Z, Squifflet JP, Ostrowski M, et al: Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial. Am J Transplant 9:2505, 2009 9. Crespo M, Mir M, Marin M, et al: De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels. Transplant Proc 41:2115, 2009 10. Anglicheau D, Legendre C, Beaune P, et al: Cytochrome P450 3A polymorphisms and immunosuppressive drugs: an update. Pharmacogenomics 8:835, 2007
T
that is within the limits of equivalence albeit 5% to 10% lower than that achieved with CT.3 However, few studies have involved heart transplant (HT) patients. Among primary orthotopic HT patients treated with SR-T,
From the Advanced Heart Failure and Heart Transplant Unit, Hospital Universitario A Coruña, A Coruña, Spain. Financial support of this research was provided by Spanish Ministry of Health and Consumer Affairs through the Carlos III Institute Cardiovascular Research Network RECAVA. Address reprint requests to Raquel Marzoa Rivas, Hospital Universitario A Coruña, Xubias 84, 15006 La Coruña, Spain. E-mail: [email protected]
0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.08.020
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2994
Transplantation Proceedings, 42, 2994 –2996 (2010)
SUSTAINED-RELEASE TACROLIMUS
smaller areas under the tacrolimus concentration-time curve have been associated with an increased rejection rate.3 Herein, we have reported the results of a retrospective analysis of the safety and efficacy of switching stable HT patients from CT to a 25% larger daily dosage of SR-T. METHODS Conversion Protocol For a patient taking a daily dose d of CT, SR-T was introduced at a daily dose of 1.25 ⫻ d. In addition to routine HT follow-up examinations, blood samples obtained at 1, 3, 7, and 12 weeks after the switch were analyzed for creatinine, glucose, tacrolimus and lipids—low-density lipoprotein, high-density lipoprotein, total cholesterol, and triglycerides. Echocardiograms were obtained every 3 or 4 months, or when there was a suspicion of allograft dysfunction.
Study Design We examined the records of all HT patients attending our center who had been converted from CT to SR-T at least 3 months prior to the study date. The variables included the CT dosage at the time of the switch; the number of dosage changes in the first 3 months after the switch to SR-T; whether and why SR-T had been suspended; graft performance; blood analysis results; blood pressures changes in antihypertensive or hypolipidemic therapy; and adverse events. The therapeutic range for tacrolimus levels was considered to be 10 to 15 ng/mL within the first year after HT, and 5 to 15 ng/mL thereafter.
Statistical Analyses Results are reported as mean values ⫾ standard deviations or as percentages, as appropriate. Between-group differences in the former were evaluated by means of Student t test. The criterion for statistical significance was P ⬍ .05. All statistical calculations were performed using SPSS 16.0.
RESULTS
The criteria for inclusion in the study were satisfied by 75 HT patients including 72% males. The switch from CT to SR-T took place at 61.7 ⫾ 48.5 months after HT; the mean patient age was 55.6 years. Postswitch follow-up was 15.7 ⫾ 4.0 months. The CT dosage at the time of the switch was 3.7 ⫾ 2.3 mg daily. Two patients (2.7%) returned to CT within 3 months of intensive surveillance because of failure of SR-T to attain therapeutic levels despite successive dosage increases. Among the other 73 patients, tacrolimus levels remained stable, with values of 8.7 ⫾ 3.2, 8.7 ⫾ 2.9, 8.3 ⫾ 2.6, and 7.5 ⫾ 2.0 mg/dL at 1, 3, 7, and 12 weeks, respectively. Twenty-three patients (31%) required no tacrolimus dosage change in the first 3 months, and another 44 (33%) required only one or two changes. In 51 patients (68%), tacrolimus levels remained within the therapeutic range throughout the 3 months, with one exception among another 11 (15%). Glycemia, creatinine, lipids, and blood pressures measured 3 months postswitch did not differ significantly from
2995
preswitch values. No patient required a change in antihypertensive or hypolipidemic therapy during this period; no echocardiographic signs of graft dysfunction were observed; and there were no cases of severe intercurrent infection. On days 9, 42, and 43 postswitch, three patients (4%) provided endomyocardial biopsy specimens compatible with cellular rejection (International Society of Heart and Lung Transplantation grade 2R in two cases and grade 1R in one), but none of them exhibited hemodynamic instability or ventricular dysfunction during the rejection episode. Subtherapeutic tacrolimus levels were not observed either before or during these episodes. The pre-episode SR-T regimen was maintained during or after the episode in all three cases. DISCUSSION
Little has been published on the use of SR-T for HT patients. In particular, there have been no sizeable randomized studies to evaluate whether and by what amount the daily tacrolimus dosage needs to be changed when switching from CT to SR-T. Our results showed that, with appropriate surveillance measures, switching a 25% larger dosage of SR-T than CT maintained both safety and efficacy, avoiding both excessive and deficient immunosuppression. Among kidney and liver transplant patients on a CT regimen, some authors4 –7 have used the same initial daily dosage of SR-T, although tacrolimus trough levels fell and in many cases subjects required dose adjustment. In de novo kidney transplant patients, SR-T has initially afforded a smaller area under tacrolimus concentration-time curves. In some cases, a 50% higher dosage had to be used to achieve adequate levels, at least during the first month after the switch from CT.8,9 The switching protocol employed in our center sought to maintain therapeutic tacrolimus levels while avoiding overimmunosuppression. No cases of rejection episodes were associated with low tacrolimus concentrations. In two patients, SR-T failed to achieve therapeutic tacrolimus levels. The causes of these failures are unknown, but they may have involved alterations in intestinal absorption and/or unfavorable cytochrome P4503A polymorphisms.9,10 In conclusion, switching from CT to a 25% larger daily dosage of SR-T was safe. For one-third of patients, it was associated with adequate tacrolimus levels without further dosage adjustment. Nevertheless, strict analytical surveillance is necessary during the initial months so as to allow dosage adjustments for the remaining two-thirds of patients and to detect the small minority of cases among whom SR-T fails to achieve therapeutic tacrolimus levels. REFERENCES 1. Pinsky BW, Takemoto SK, Lentine KL, et al: Transplant outcomes and economic costs associated with patient noncompliance to immunosuppression. Am J Transplant 9:2597, 2009 2. O’Grady JG, Asderakis A, Bradley R, et al: Multidisciplinary insights into optimizing adherence after solid organ transplantation. Transplantation 89:627, 2010 3. Australian Therapeutic Goods Administration: Australian public assessment report for tacrolimus. Department of Health and
2996 Ageing, May 2010. Available at: www.tga.gov.au/pmeds/auspar/ auspar-prograf-xl.pdf. Accessed June 11, 2010 4. Gallego-Valcarce E, Ortega-Cerrato A, Llamas-Fuentes F, et al: Conversion to tacrolimus extendedrelease formulation: shortterm clinical results. Transplant Proc 41:2326, 2009 5. Diez Ojea B, Alonso Alvarez M, Aguado Fernández S, et al: Three-month experience with tacrolimus once-daily regimen in stable renal allografts. Transplant Proc 41:2323, 2009 6. First MR: First clinical experience with the new once-daily formulation of tacrolimus. Ther Drug Monit 30:159, 2008 7. Marin-Gomez LM, Gomez-Bravo MA, Alamo-Martinez JA, et al: Evaluation of clinical safety of conversion to Advagraf
MARZOA-RIVAS, PANIAGUA-MARTÍN, BARGE-CABALLERO ET AL therapy in liver transplant recipients: observational study. Transplant Proc 41:2184, 2009 8. Wlodarczyk Z, Squifflet JP, Ostrowski M, et al: Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial. Am J Transplant 9:2505, 2009 9. Crespo M, Mir M, Marin M, et al: De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels. Transplant Proc 41:2115, 2009 10. Anglicheau D, Legendre C, Beaune P, et al: Cytochrome P450 3A polymorphisms and immunosuppressive drugs: an update. Pharmacogenomics 8:835, 2007