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De Novo Prograf Versus De Novo Advagraf: Are Trough Level Profile Curves Similar?
De Novo Prograf Versus De Novo Advagraf: Are Trough Level Profile Curves Similar? E. Sarvary*, L. Wagner, G. Telkes, Gy. Gaman, M. Varga, I. Gaal, Zs. Mathe, R. Chmel, I. Fehervari, and R.M. Langer Semmelweis Medical University, Transplantation and Surgical Clinic, Budapest, Hungary
ABSTRACT Background. According to the clinical trials, Advagraf (ADV) has efficacy and safety profile similar to Prograf (PROG). The aim of this study was to compare the graft functions, dosages, and tacrolimus (TAC) trough level profile curves of patients on de novo PROG and ADV therapy. Methods. The ADV group included 39 de novo renal cases who had received initial immunosuppression (IS) with once-daily TAC (1 0.2 mg/kg from day1 after transplantation). We compared them with a PROG group of 38 transplant patients who received equivalent IS with twice-daily TAC (2 0.1 mg/kg from day1). In both groups, the IS was combined with antimetabolites and steroids. The mean follow-up time was similar (13.5 7 days) in both groups after renal transplantation until the emission of the patients from our clinic. Results. TAC mean total daily dose was reduced and whole-blood trough levels decreased over the time in early postoperative days. Only on day 3 and day 4 after transplant, a significant higher adjustment in the ADV dosage was necessary to achieve sufficient TAC trough levels. The average TAC trough level profile curves were similar in PROG and ADV groups, but the individual curves were very different. Mainly in patients on ADV therapy, the initial concentrations were often >30 ng/mL, and in some cases on the 9th posttransplant day decreased to <5 ng/mL, then slowly increased into the required therapeutic range. Conclusions. The results demonstrate that patients after renal transplantation can be safely treated de novo with ADV. Setting the required therapeutic TAC blood levels may require more attention to avoid the “fluctuations” of trough level profile curve during the early postoperative period. Our data suggest that dose adjustment of ADV can be carried out more carefully compared with PROG on the basis of clinical symptoms and the value of TAC blood levels to avoid acute rejection and toxicity.
T
ACROLIMUS (TAC) is available in different oral formulations around the world. Advagraf (ADV; Astellas Pharma Europe Ltd, Gardabaer, Iceland), a new, extended-release formulation of TAC, allows once-daily administration in the morning [1,2] while showing a similar efficacy and safety profile as the conventional Prograf (PROG; Astellas Pharma Europe Ltd), which is prescribed twice daily [3,4]. De novo renal transplant recipients need higher doses of ADV than PROG, but this difference tends toward non-significance over time [5]. To date, the trough-level profile curves of TAC at de novo renal-
transplanted patients through the use of de novo ADV or PROG therapy have not been analyzed together. The de novo ADV therapy of renal transplants started in January 2013 in our clinic. We were interested in which patient groups (ADV vs PROG) it was “easier” to achieve
*Address correspondence to Eniko Sarvary, PhD, Semmelweis Medical University, Transplantation and Surgical Clinic, H-1083 Baross Str. 23-25, Budapest, Hungary. E-mail: eniko.sarvary@ gmail.com
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2014.05.061
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2164
Transplantation Proceedings, 46, 2164e2167 (2014)
DE NOVO PROGRAF VERSUS DE NOVO ADVAGRAF
and maintain the required therapeutic blood levels of TAC (10e12 ng/mL) in the early postoperative period. PATIENT AND METHODS Data of adult patients (n ¼ 77) with end-stage renal disease were investigated. The age (44 11 years; 18e72 years) and sex (male, 53%; female, 47%) division was similar within the two groups. The ADV group included 39 de novo renal cases who received initial immunosuppression (IS) with once-daily TAC in the morning (0.2 mg/kg from day 1 after transplantation) between January and September 2013. We compared them with the PROG group of 38 transplant patients who received equivalent IS with twice-daily TAC (2 0.1 mg/kg body wt per from day 1) between May 2012 and December 2012 at our institution. In both groups, the IS was combined with antimetabolites and steroids. According to the protocol, the Mycophenolate Mophetil/Cellcept (Roche) or Myfortic (Novartis, Hoffman-La Roche Ltd., Basel, Switzerland) was given orally from postoperative day 1. The PROG and ADV dosages, TAC trough concentrations (Cmin), graft function parameters (serum creatinine, estimated glomerular filtration rate), and number of rejection episodes were examined. Blood samples for immunosuppressive drug monitoring were taken before dosing (in EDTA anticoagulant) of 77 transplant patients, and TAC trough levels were determined with the use of Chemiluminescent Microparticle ImmunoAssay (CMIA; Architect System; ABBOTT [6,7].). The Architect TAC assay was designed to have precision of 10% total coefficient of variation and to have a mean recovery of 100% 10% of expected value. The lower limit of quantification for TAC was 1.5 ng/mL. The Cmin levels were measured every 3rd day in the early postoperative period until emission to home from the clinic. The expected target TAC trough levels were between 10 to 12 ng/mL during the first 2e3 weeks of posttransplantation. The TAC dose adjustment was based on clinical symptoms and TAC level monitoring results. The mean follow-up time was 13.5 7 days after transplantation until the emission of the patients from our clinic. Descriptive analysis, c2, Student t test, and Mann-Whitney U test were used to analyze our data (SPSS 15.0). Differences in TAC trough levels were analyzed by means of t tests at each time point at PROG and ADV patients groups.
RESULTS
We did not observe significant differences between the two groups in age and sex distribution, body mass index, and duration of hospitalization. The ADV was as well tolerated as PROG in the early postoperative days. TAC mean total daily dose and whole-blood trough levels decreased over the time in the early postoperative days, especially in the first week. We found that recipients on de novo ADV therapy needed significantly higher TAC doses only on the 3rd (P ¼ .022) and the 4th (P ¼ .046) days after transplantation. The mean TAC trough level profile curves were similar in PROG and ADV groups. In contrast, the individual curves were very different between the two groups. Mostly in the early postoperative first week, the TAC levels were higher and the trough level profile curves showed more overshoots of patients on ADV therapy. In the ADV group, the initial TAC concentrations were found more often >30 ng/mL in the ADV group compared with the PROG group. In some cases on the 9th posttransplant day, the TAC levels
2165
decreased to <5 ng/mL, then slowly increased into the required therapeutic range. The profile curves showed a smoother (less fluctuating) graph in patients receiving PROG. On the 3rd posttransplant day, >70% of patients with ADV were over-immunosuppressed, on the basis of the TAC profile curves. The Cmin of TAC levels were higher than the therapeutic range as opposed to the PROG group, in which only half of the patients’ TAC concentrations were higher than the expected concentration. In the case of the ADV users, the TAC level was under the expected level on the postoperative 9th and sometimes even 12th day. According to the trough level profile curves, the parameters of graft functions showed the best results, when the blood drug concentration reached the therapeutic range as soon as possible and stayed continuously in it. The number of dose adjustments were significantly (P < .0001) higher in the PROG group (n ¼ 5, 17 1.6) compared with the ADV (n ¼ 3, 29 1.7) group during the early postoperative hospitalization. Both treatment groups showed equally wellmaintained renal function (mean creatinine clearance was approximately 49 11 mL/min/1.73 m2 at the time of emission from the clinic after the transplantation). There was no significant difference between the graft function; most grafts (84%) functioned very well, and <20% of the transplanted kidneys started to function slowly after the surgery in both patient groups. After the individual blood level profile curves are analyzed, it can be stated as a result that in the case (24%) of the patients on de novo ADV therapy, the TAC trough concentrations were constantly below the therapeutic range; however, at 10% within the patients, relatively high TAC concentrations (>12 ng/mL) were measured in the whole period of the hospitalization. In 13% of the patients, the C(min) level values were absolutely ideal, as the measured TAC levels were within the therapeutic range. Compared with the PROG group, 3% of the TAC profile curves were under and 28% of them were above the required therapeutic range during the whole investigated postoperative period. In 50% of the patients, the C(min) values decreased to <10 ng/mL on the 9th, sometimes even on the 12th postoperative days also. In 7 cases, acute rejection (ARE) occurred in the ADV group. The reported rejections were diagnosed between postoperative days 3 and 9. In the investigated patients on PROG therapy, ARE was diagnosed in 4 cases between postoperative days 6 and 12. DISCUSSION
PROG and ADV have been shown to be bioequivalent, according to the typically used European Medicines Agency and US Food and Drug Administration criteria [8]. The new extended-release formulation of TAC offers a great advantage for the quality of life of transplant recipients, facilitating treatment compliance [5]. Among de novo renal cases, the new once-daily formulation (ADV) of TAC offered a short-term efficacy profile similar to the twice-daily TAC [9]. In conclusion, the new once-daily formulation of
2166
SARVARY, WAGNER, TELKES ET AL
Fig 1. Therapeutic drug monitoring of tacrolimus (TAC) concentrations in the early postoperative days in renal-transplanted patients on : Thick line indicates the expected therapeutic range of TAC level (10e12 ng/mL) in our clinic. de novo PROG and ADV therapy. : Dashed circle shows the initial high TAC concentrations on 3rd and 6th postoperative days in patients on ADV therapy. : Dashed arrow shows the dropped TAC concentrations on the 9th postoperative day in patients on ADV therapy. Abbreviations: ADV, Advagraf; PROG, Prograf; TAC, tacrolimus.
TAC offers a useful short-term efficacy and safety profile [10]. According to our results, it was necessary to use higher doses of ADV than PROG to achieve similar trough levels only in the 3rd and the 4th days after transplantation. Our data provide evidence that kidney transplant patients can be maintained on ADV therapy immediately after transplantation; however, the ADV dose adjustment can be performed more carefully compared with the traditional PROG dosing. A longer time was required to reach the steady state of TAC blood level at therapy on ADV compared with PROG. For this reason, at our clinic, the dose modification and TAC through level measurements are rarely recommended (every 3rd day) compared with patients on PROG therapy, in whom the dose modification and trough concentration measurements were carried out more frequently (every 2nd day) during the early postoperative period. During the first week, target TAC trough levels were hardly achieved; usually, the TAC levels were higher than the desired therapeutic range on the 3rd day and often on the 6th day after transplantation. In the first postoperative week, the TAC Cmin of 70% of the ADV patients was much higher than expected. In day 9 after transplantation, trough levels declined below determined target levels despite retained ADV dosage (Fig 1). Excellent graft survival rates were achieved with both formulations. According to Krämer et al [11], ARE was well controlled, although the incidence of ARE was numerically higher in patients receiving ADV but was not significantly different compared with the patients receiving ADV and PROG therapy. According to our results, the incidence of ARE was also numerically higher in patients receiving ADV, but, because of the small number of cases, it does not allow conclusions to be drawn. The clinicians did not experience a significantly higher number of acute rejection episodes. This ARE irregularity might have been due to random selection of patients. Further studies are needed to investigate the incidence of ARE in the patients on de novo ADV therapy. The results that come from the individual ADV trough level curve profiles may help to
achieve the therapeutic range of TAC level as soon as possible after transplantation. The results demonstrate that patients after renal transplantation can be safely treated de novo with ADV. Setting the required therapeutic TAC blood levels may require more attention to avoid the “fluctuations” of trough level profile curve during the early postoperative period. Our data suggest that dose adjustment of ADV can be carried out more carefully compared with PROG on the basis of clinical symptoms and the value of TAC blood levels to avoid acute rejection and toxicity. ACKNOWLEDGMENTS The authors gratefully thank our lab assistants for the help of the sample collecting, handling, and tacrolimus level measurements.
REFERENCES [1] Min Sang-Il, Ha Jongwon, Kim Yon Su, et al. Therapeutic equivalence and pharmacokinetics of generic tacrolimus formulation in de novo kidney transplant patients. Nephrol Dial Transplant 2013;28:3110e9. [2] Roy First M, Fitzsimmons WE. Modified release tacrolimus. Yonsei Med J 2004;45:1127. [3] Diez Ojea B, Alonso Alvarez M, Aguado Fernadez S, et al. Three-month experience with tacrolimus once-daily regimen in stable renal allografts. Transplant Proc 2009;41:2323. [4] Wente MN, Sauer P, Mehrabi A, et al. Review of the clinical experience with a modified release form of tacrolimus [FK506E (MR4)] in transplantation. Clin Transplant 2006; 20(Suppl 17):80. [5] 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 2009;41:2115e7. [6] Jusko WJ. Analysis of tacrolimus (FK 506) in relation to therapeutic drug monitoring. Ther Drug Monit 1995;17:596e601. [7] Laskow DA, Vincenti F, Neylan JF, et al. An open-label, concentration-ranging trial of FK506 in primary kidney transplantation: a report of the United States Multicenter FK506 Kidney Transplant Group. Transplantation 1996;62:900e5.
DE NOVO PROGRAF VERSUS DE NOVO ADVAGRAF [8] Barraclough KA, Isbel NM, Johnson DW, et al. Once- versus twice-daily tacrolimus: are the formulations truly equivalent? Drugs 2011;71:1561e77. [9] van Hooff JP, Alloway RR, Trunecka P, et al. Four-year 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:E1e12.
2167 [10] Jelassi ML, Lefeuvre S, Karras A, et al. Therapeutic drug monitoring in de novo kidney transplant receiving the modifiedrelease once-daily tacrolimus. Transplant Proc 2011;43:491e4. [11] Krämer BK, Charpentier B, Bäckman L, et al. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant 2010;10:2632e43.
ABSTRACT Background. According to the clinical trials, Advagraf (ADV) has efficacy and safety profile similar to Prograf (PROG). The aim of this study was to compare the graft functions, dosages, and tacrolimus (TAC) trough level profile curves of patients on de novo PROG and ADV therapy. Methods. The ADV group included 39 de novo renal cases who had received initial immunosuppression (IS) with once-daily TAC (1 0.2 mg/kg from day1 after transplantation). We compared them with a PROG group of 38 transplant patients who received equivalent IS with twice-daily TAC (2 0.1 mg/kg from day1). In both groups, the IS was combined with antimetabolites and steroids. The mean follow-up time was similar (13.5 7 days) in both groups after renal transplantation until the emission of the patients from our clinic. Results. TAC mean total daily dose was reduced and whole-blood trough levels decreased over the time in early postoperative days. Only on day 3 and day 4 after transplant, a significant higher adjustment in the ADV dosage was necessary to achieve sufficient TAC trough levels. The average TAC trough level profile curves were similar in PROG and ADV groups, but the individual curves were very different. Mainly in patients on ADV therapy, the initial concentrations were often >30 ng/mL, and in some cases on the 9th posttransplant day decreased to <5 ng/mL, then slowly increased into the required therapeutic range. Conclusions. The results demonstrate that patients after renal transplantation can be safely treated de novo with ADV. Setting the required therapeutic TAC blood levels may require more attention to avoid the “fluctuations” of trough level profile curve during the early postoperative period. Our data suggest that dose adjustment of ADV can be carried out more carefully compared with PROG on the basis of clinical symptoms and the value of TAC blood levels to avoid acute rejection and toxicity.
T
ACROLIMUS (TAC) is available in different oral formulations around the world. Advagraf (ADV; Astellas Pharma Europe Ltd, Gardabaer, Iceland), a new, extended-release formulation of TAC, allows once-daily administration in the morning [1,2] while showing a similar efficacy and safety profile as the conventional Prograf (PROG; Astellas Pharma Europe Ltd), which is prescribed twice daily [3,4]. De novo renal transplant recipients need higher doses of ADV than PROG, but this difference tends toward non-significance over time [5]. To date, the trough-level profile curves of TAC at de novo renal-
transplanted patients through the use of de novo ADV or PROG therapy have not been analyzed together. The de novo ADV therapy of renal transplants started in January 2013 in our clinic. We were interested in which patient groups (ADV vs PROG) it was “easier” to achieve
*Address correspondence to Eniko Sarvary, PhD, Semmelweis Medical University, Transplantation and Surgical Clinic, H-1083 Baross Str. 23-25, Budapest, Hungary. E-mail: eniko.sarvary@ gmail.com
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2014.05.061
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2164
Transplantation Proceedings, 46, 2164e2167 (2014)
DE NOVO PROGRAF VERSUS DE NOVO ADVAGRAF
and maintain the required therapeutic blood levels of TAC (10e12 ng/mL) in the early postoperative period. PATIENT AND METHODS Data of adult patients (n ¼ 77) with end-stage renal disease were investigated. The age (44 11 years; 18e72 years) and sex (male, 53%; female, 47%) division was similar within the two groups. The ADV group included 39 de novo renal cases who received initial immunosuppression (IS) with once-daily TAC in the morning (0.2 mg/kg from day 1 after transplantation) between January and September 2013. We compared them with the PROG group of 38 transplant patients who received equivalent IS with twice-daily TAC (2 0.1 mg/kg body wt per from day 1) between May 2012 and December 2012 at our institution. In both groups, the IS was combined with antimetabolites and steroids. According to the protocol, the Mycophenolate Mophetil/Cellcept (Roche) or Myfortic (Novartis, Hoffman-La Roche Ltd., Basel, Switzerland) was given orally from postoperative day 1. The PROG and ADV dosages, TAC trough concentrations (Cmin), graft function parameters (serum creatinine, estimated glomerular filtration rate), and number of rejection episodes were examined. Blood samples for immunosuppressive drug monitoring were taken before dosing (in EDTA anticoagulant) of 77 transplant patients, and TAC trough levels were determined with the use of Chemiluminescent Microparticle ImmunoAssay (CMIA; Architect System; ABBOTT [6,7].). The Architect TAC assay was designed to have precision of 10% total coefficient of variation and to have a mean recovery of 100% 10% of expected value. The lower limit of quantification for TAC was 1.5 ng/mL. The Cmin levels were measured every 3rd day in the early postoperative period until emission to home from the clinic. The expected target TAC trough levels were between 10 to 12 ng/mL during the first 2e3 weeks of posttransplantation. The TAC dose adjustment was based on clinical symptoms and TAC level monitoring results. The mean follow-up time was 13.5 7 days after transplantation until the emission of the patients from our clinic. Descriptive analysis, c2, Student t test, and Mann-Whitney U test were used to analyze our data (SPSS 15.0). Differences in TAC trough levels were analyzed by means of t tests at each time point at PROG and ADV patients groups.
RESULTS
We did not observe significant differences between the two groups in age and sex distribution, body mass index, and duration of hospitalization. The ADV was as well tolerated as PROG in the early postoperative days. TAC mean total daily dose and whole-blood trough levels decreased over the time in the early postoperative days, especially in the first week. We found that recipients on de novo ADV therapy needed significantly higher TAC doses only on the 3rd (P ¼ .022) and the 4th (P ¼ .046) days after transplantation. The mean TAC trough level profile curves were similar in PROG and ADV groups. In contrast, the individual curves were very different between the two groups. Mostly in the early postoperative first week, the TAC levels were higher and the trough level profile curves showed more overshoots of patients on ADV therapy. In the ADV group, the initial TAC concentrations were found more often >30 ng/mL in the ADV group compared with the PROG group. In some cases on the 9th posttransplant day, the TAC levels
2165
decreased to <5 ng/mL, then slowly increased into the required therapeutic range. The profile curves showed a smoother (less fluctuating) graph in patients receiving PROG. On the 3rd posttransplant day, >70% of patients with ADV were over-immunosuppressed, on the basis of the TAC profile curves. The Cmin of TAC levels were higher than the therapeutic range as opposed to the PROG group, in which only half of the patients’ TAC concentrations were higher than the expected concentration. In the case of the ADV users, the TAC level was under the expected level on the postoperative 9th and sometimes even 12th day. According to the trough level profile curves, the parameters of graft functions showed the best results, when the blood drug concentration reached the therapeutic range as soon as possible and stayed continuously in it. The number of dose adjustments were significantly (P < .0001) higher in the PROG group (n ¼ 5, 17 1.6) compared with the ADV (n ¼ 3, 29 1.7) group during the early postoperative hospitalization. Both treatment groups showed equally wellmaintained renal function (mean creatinine clearance was approximately 49 11 mL/min/1.73 m2 at the time of emission from the clinic after the transplantation). There was no significant difference between the graft function; most grafts (84%) functioned very well, and <20% of the transplanted kidneys started to function slowly after the surgery in both patient groups. After the individual blood level profile curves are analyzed, it can be stated as a result that in the case (24%) of the patients on de novo ADV therapy, the TAC trough concentrations were constantly below the therapeutic range; however, at 10% within the patients, relatively high TAC concentrations (>12 ng/mL) were measured in the whole period of the hospitalization. In 13% of the patients, the C(min) level values were absolutely ideal, as the measured TAC levels were within the therapeutic range. Compared with the PROG group, 3% of the TAC profile curves were under and 28% of them were above the required therapeutic range during the whole investigated postoperative period. In 50% of the patients, the C(min) values decreased to <10 ng/mL on the 9th, sometimes even on the 12th postoperative days also. In 7 cases, acute rejection (ARE) occurred in the ADV group. The reported rejections were diagnosed between postoperative days 3 and 9. In the investigated patients on PROG therapy, ARE was diagnosed in 4 cases between postoperative days 6 and 12. DISCUSSION
PROG and ADV have been shown to be bioequivalent, according to the typically used European Medicines Agency and US Food and Drug Administration criteria [8]. The new extended-release formulation of TAC offers a great advantage for the quality of life of transplant recipients, facilitating treatment compliance [5]. Among de novo renal cases, the new once-daily formulation (ADV) of TAC offered a short-term efficacy profile similar to the twice-daily TAC [9]. In conclusion, the new once-daily formulation of
2166
SARVARY, WAGNER, TELKES ET AL
Fig 1. Therapeutic drug monitoring of tacrolimus (TAC) concentrations in the early postoperative days in renal-transplanted patients on : Thick line indicates the expected therapeutic range of TAC level (10e12 ng/mL) in our clinic. de novo PROG and ADV therapy. : Dashed circle shows the initial high TAC concentrations on 3rd and 6th postoperative days in patients on ADV therapy. : Dashed arrow shows the dropped TAC concentrations on the 9th postoperative day in patients on ADV therapy. Abbreviations: ADV, Advagraf; PROG, Prograf; TAC, tacrolimus.
TAC offers a useful short-term efficacy and safety profile [10]. According to our results, it was necessary to use higher doses of ADV than PROG to achieve similar trough levels only in the 3rd and the 4th days after transplantation. Our data provide evidence that kidney transplant patients can be maintained on ADV therapy immediately after transplantation; however, the ADV dose adjustment can be performed more carefully compared with the traditional PROG dosing. A longer time was required to reach the steady state of TAC blood level at therapy on ADV compared with PROG. For this reason, at our clinic, the dose modification and TAC through level measurements are rarely recommended (every 3rd day) compared with patients on PROG therapy, in whom the dose modification and trough concentration measurements were carried out more frequently (every 2nd day) during the early postoperative period. During the first week, target TAC trough levels were hardly achieved; usually, the TAC levels were higher than the desired therapeutic range on the 3rd day and often on the 6th day after transplantation. In the first postoperative week, the TAC Cmin of 70% of the ADV patients was much higher than expected. In day 9 after transplantation, trough levels declined below determined target levels despite retained ADV dosage (Fig 1). Excellent graft survival rates were achieved with both formulations. According to Krämer et al [11], ARE was well controlled, although the incidence of ARE was numerically higher in patients receiving ADV but was not significantly different compared with the patients receiving ADV and PROG therapy. According to our results, the incidence of ARE was also numerically higher in patients receiving ADV, but, because of the small number of cases, it does not allow conclusions to be drawn. The clinicians did not experience a significantly higher number of acute rejection episodes. This ARE irregularity might have been due to random selection of patients. Further studies are needed to investigate the incidence of ARE in the patients on de novo ADV therapy. The results that come from the individual ADV trough level curve profiles may help to
achieve the therapeutic range of TAC level as soon as possible after transplantation. The results demonstrate that patients after renal transplantation can be safely treated de novo with ADV. Setting the required therapeutic TAC blood levels may require more attention to avoid the “fluctuations” of trough level profile curve during the early postoperative period. Our data suggest that dose adjustment of ADV can be carried out more carefully compared with PROG on the basis of clinical symptoms and the value of TAC blood levels to avoid acute rejection and toxicity. ACKNOWLEDGMENTS The authors gratefully thank our lab assistants for the help of the sample collecting, handling, and tacrolimus level measurements.
REFERENCES [1] Min Sang-Il, Ha Jongwon, Kim Yon Su, et al. Therapeutic equivalence and pharmacokinetics of generic tacrolimus formulation in de novo kidney transplant patients. Nephrol Dial Transplant 2013;28:3110e9. [2] Roy First M, Fitzsimmons WE. Modified release tacrolimus. Yonsei Med J 2004;45:1127. [3] Diez Ojea B, Alonso Alvarez M, Aguado Fernadez S, et al. Three-month experience with tacrolimus once-daily regimen in stable renal allografts. Transplant Proc 2009;41:2323. [4] Wente MN, Sauer P, Mehrabi A, et al. Review of the clinical experience with a modified release form of tacrolimus [FK506E (MR4)] in transplantation. Clin Transplant 2006; 20(Suppl 17):80. [5] 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 2009;41:2115e7. [6] Jusko WJ. Analysis of tacrolimus (FK 506) in relation to therapeutic drug monitoring. Ther Drug Monit 1995;17:596e601. [7] Laskow DA, Vincenti F, Neylan JF, et al. An open-label, concentration-ranging trial of FK506 in primary kidney transplantation: a report of the United States Multicenter FK506 Kidney Transplant Group. Transplantation 1996;62:900e5.
DE NOVO PROGRAF VERSUS DE NOVO ADVAGRAF [8] Barraclough KA, Isbel NM, Johnson DW, et al. Once- versus twice-daily tacrolimus: are the formulations truly equivalent? Drugs 2011;71:1561e77. [9] van Hooff JP, Alloway RR, Trunecka P, et al. Four-year 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:E1e12.
2167 [10] Jelassi ML, Lefeuvre S, Karras A, et al. Therapeutic drug monitoring in de novo kidney transplant receiving the modifiedrelease once-daily tacrolimus. Transplant Proc 2011;43:491e4. [11] Krämer BK, Charpentier B, Bäckman L, et al. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant 2010;10:2632e43.