Saudi Journal of Kidney Diseases and Transplantation

ORIGINAL ARTICLE
Year
: 2018  |  Volume : 29  |  Issue : 6  |  Page : 1267--1273

Comparative analysis for optimizing the modified release tacrolimus (Advagraf) after kidney transplantation: A prospective randomized trial


Mohamed Adel Bakr, Ayman Maher Nagib, Ahmed Farouk Donia, Ahmed Abdelfattah Denewar, Mohamed Megahid Abu-Elmagd, Mohamed Hamed Abbas, Ahmed Mansour Abdel-Rahman, Mohamed Elsayed Mashaly, Mohamed Mohamed Elsaftawy, Mohamed Ahmed Ghoneim 
 Department of Dialysis and Transplantation, The Urology -Nephrology Center, Mansoura University, Mansoura, Egypt

Correspondence Address:
Prof. Mohamed Adel Bakr
Department of Dialysis and Transplantation, The Urology -Nephrology Center, Mansoura University, Mansoura
Egypt

Abstract

Immunosuppression management in clinical transplantation aims to balance delivery of efficacy against adverse reactions using therapeutic drug monitoring. Adherence to posttransplant immunosuppressive medications and minimizing variability in drug exposure are important considerations in preventing rejection and maximizing overall transplant outcomes. The availability of once-daily tacrolimus may add a potential benefit by simplifying immunosuppressive regimens, though improving compliance among transplant recipients. The aim of our study is to investigate the safety and efficacy of the once-daily formulation of tacrolimus (Advagraf) against the usually used twice daily tablets (Prograf). A prospective randomized trial 1:2 was designed for 99 consecutive live-related renal transplant recipients who received their grafts at a single center (study group, Advagraf, 33 recipients and control group, Prograf, 66 recipients). The demographic data were homogeneous among both groups regarding donors and patients’ characteristics. Posttransplant hypertension, infection, malignancy, and diabetes mellitus were comparable among both groups. Renal function and rejection episodes showed no statistical significance among recipients of both groups. Despite slight higher Advagraf unit doses, there was no statistical difference regarding the tacrolimus trough levels, between the two groups. Our singlecenter experience revealed that the availability of once-daily tacrolimus formulation could give potential benefit of improved medication compliance and better allograft outcomes by decreasing pill burden and thereby simplifying dosing schedule, Advagraf was non-inferior to twice-daily tacrolimus regarding safety and efficacy. Although being nonsignificant, a trend for better kidney function was noted in this short-term study in the Advagraf group, so long-term follow-up is needed to verify this.



How to cite this article:
Bakr MA, Nagib AM, Donia AF, Denewar AA, Abu-Elmagd MM, Abbas MH, Abdel-Rahman AM, Mashaly ME, Elsaftawy MM, Ghoneim MA. Comparative analysis for optimizing the modified release tacrolimus (Advagraf) after kidney transplantation: A prospective randomized trial.Saudi J Kidney Dis Transpl 2018;29:1267-1273


How to cite this URL:
Bakr MA, Nagib AM, Donia AF, Denewar AA, Abu-Elmagd MM, Abbas MH, Abdel-Rahman AM, Mashaly ME, Elsaftawy MM, Ghoneim MA. Comparative analysis for optimizing the modified release tacrolimus (Advagraf) after kidney transplantation: A prospective randomized trial. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2019 Jan 17 ];29:1267-1273
Available from: http://www.sjkdt.org/text.asp?2018/29/6/1267/248303


Full Text

 Introduction



Immunosuppression management in clinical transplantation aims to balance delivery of efficacy against adverse reactions using therapeutic drug monitoring. The other important aspect of managing immunosuppression is ensuring compliance by the transplant patients in order to sustain an allograft free from rejection.[1] Overall acceptability of a regimen, convenience of dosing, and tolerability of individual drugs or regimens frequently impact patients’ medications compliance.[2] Hence, most studies on immunosuppressive agents focus on efficacy and safety, with the goal of achieving the best possible allograft function with minimal adverse effects.

Over the years, immunosuppressive regimens utilized in transplantation have evolved. In current practice, the most commonly used immunosuppressive regimen includes a calcineurin inhibitor (cyclosporine, tacrolimus) and an antimetabolite [mycophenolate mofetil (MMF), azathioprine], with or without cortico-steroids.[3] Increasing availability of a broad range of immunosuppressive medications and formulations open the possibilities of designing regimens that achieve the best possible graft outcome along with minimal adverse effects while, at the same time, maximizing treatment adherence among transplant recipients.

Conventional immunosuppression in the modern era involves twice-daily oral dosing of calcineurin inhibitors and antiproliferative such as MMF. This need for twice-daily dosing schedules has been associated with non-adherence. Previous reviews directed at recipients transplanted between the late 1980s and mid-2000s showed that the prevalence of nonadherence to immunosuppressive medications averaged about 25%.[2] This non-adherence to medications was felt to contribute to about 20% of late acute rejection episodes and 16%–36% of graft losses.[2] It would, therefore, be reasonable to expect that a simplified immunosuppressive regimen that involves less frequent drug dosing would improve both patients’ medication compliance and long-term allograft outcomes.[1],[4]

The availability of once-daily tacrolimus formulation could thus offer the potential benefit of improved medication compliance and possibly better allograft outcomes by decreasing pill burden and thereby simplifying dosing schedule. Since there is more extensive experience in the use of the twice-daily tacrolimus formulation in clinics, the increased utilization of once-daily tacrolimus demands a review of evidence that this formulation is comparable, or non-inferior if not superior, to twice-daily tacrolimus regarding safety and efficacy. Studies on medication compliance showed that patients converted to once-daily tacrolimus had improved adherence regarding drug taking, timing, and dosing. There was also a trend toward decrease in missed doses with once-daily tacrolimus.[5]

 Aim of the work



The aim of this work is to compare the efficacy and safety profiles of the two tacrolimus formulations therapy regimens. Renal function is assessed by the change in serum creatinine and estimated glomerular filtration rate according to Cockroft and Gault formula between the two therapy regimens after 12-month posttransplantation.

 Patients and Methods



Ninety-nine patients with end-stage renal disease, who underwent live-donor renal allo-transplant between June 2013 and July 2014, were enrolled into prospective randomized 1:2 controlled study. Patients were assigned either to receive Advagraf (study group n = 33 patients) or to receive Prograf (control group n = 66 patients). Male or female recipients (age range: 18–56 years) with end-stage kidney disease who were the candidates for a first renal transplant from a living donor, aged 21–60 years, with compatible ABO blood groups were included in the study. We excluded recipients with high immunologic risk, defined as zero DR matching, positive cross-match, presence of donor-specific antibodies or patients with retransplantation. Patients and donors were fully informed and provided written consent. The study is conformed to the ethical guidelines of the 1975 Helsinki Declaration and Istanbul declaration.

Patients in both groups received induction therapy in the form of anti-CD25 (Basiliximab) 20 mg, 1 h before the operation and on the fourth day. All patients received steroid, Methylprednisolone 500 mg intravenous (IV) bolus day 0 then, 125 mg IV bolus day-1 post-operative. Then, prednisone or equivalent day 2: 14, 20 mg PO, day 15: 28, 15 mg PO, day 29: 42, 10 mg PO, day 43: 90, 5 mg PO, from day 91, and ≤5 mg PO. In the study group, each patient received Advagraf (once daily tacrolimus) in a dose of 0.15 mg/kg/day, orally. The control patients received Prograf (twice daily tacrolimus) with the same dose, and it was adjusted to achieve target whole-blood trough levels of 8–10 ng/mL during the first four weeks and 6–8 ng/mL thereafter. Tacrolimus trough concentrations in whole blood were measured by an IMx analyzer (Abbott Laboratories, Abbott Park, IL, USA). MMF was administered to every patient at 1 g twice daily, and decreased to 750 mg twice daily after four weeks according to our protocol until the end of the study. All episodes of rejection were verified by biopsy and graded using the BANFF 2011 working classifica-tion.[6] Rejection episodes were treated primarily with methylprednisolone 500 mg IV for five consecutive days. In case of a steroid-resistant rejection, antithymocyte globulin was added.

Patient monitoring

In each follow-up visit, every patient was subjected to a clinical examination with special stress on blood pressure, BMI. Laboratory assessments included creatinine and creatinine clearance using the Cockcroft and Gault formula, tacrolimus whole blood trough levels, fasting, and postprandial venous plasma glucose levels.

Study drug formulations

0.5, 1, 3, and 5 mg Advagraf capsules, and 0.5, 1, and 5 mg Prograf capsules.

Duration of treatment and duration of study

The duration of study enrollment period was 12 months.

Concomitant medications

All concomitant immunosuppressive medications such as steroids and MMF used in combination with either the Prograf or Advagraf regimen at start of study should follow the dosing directions described in the treatment section, unless, if changes are required due to medical needs.

Prohibited concomitant therapy

All non-licensed medications and study medication administered as part of another clinical study were prohibited. They had to be discontinued 28 days at the latest before enrolment. After enrollment, immunosuppres-sive treatment with antibody induction therapy (other than described), azathioprine, and sirolimus were not permitted.

Endpoints

Primary efficacy variable: Renal function as assessed by calculated creatinine clearance at month 12 according to the Cockcroft and Gault formula.

Secondary efficacy and safety variable

Frequency of biopsy-proven acute rejection episodes, patient and graft survival, incidence of adverse events, and renal dysfunction.

 Statistical Analysis



The findings were recorded, tabulated, and analyzed using Statistical Package for the Social Science (SPSS) version 16.0 for windows (SPSS Inc., Chicago, IL, USA). T-test was used to compare the continuous data between the two groups, while non-continuous data were compared using the Mann–Whitney U test. Categorical data were compared using chi-square test. Qualitative data were displayed in cross tabulation and quantitative data were described regarding arithmetic mean ± standard deviation. Bivariate techniques were used for initial evaluation of contrasts. The graft and patient survival were computed using the Kaplan-Meier technique. P <0.05 was considered statistically significant.

 Results



Donor and recipient demographic characteristics are shown in [Table 1]. The majority of recipients were men in their late twenties; on the other hand, more than half of the donors were women in their mid-thirties. In addition, the two groups were homogenous regarding donor age and sex, recipient age, and sex, prior blood transfusion, hepatitis C virus status, original kidney diseases, tissue typing, and pretransplant hypertension. No preformed antibodies against donor antigens were detected in the pretransplant cross-match of any of the studied patients. For the study group, the mean tacrolimus doses were 4.5 ± 2.4 mg/day, the mean trough levels were 6.5 ± 3.8 ng/mL and mean serum creatinine were 1.03 ± 0.23 mg/ dL. Regarding the rejection episodes, 28 patients (85%) of the study group enjoyed a rejection-free study period while one patient (3%) had repeated rejections and the remaining four patients (12%) suffered one rejection episode each. One of our recipients was subjected to basal cell carcinoma excision and continued the follow-up till nine months. Posttransplant complications encountered are given in [Table 2]. Surgical complications in the form of urinary leakage and peri-graft collections were seen in 3% and 6%, respectively [Table 2]. All of our patients are living with functioning grafts. One year after the transplant, the renal function and posttransplant complications were comparable in both groups [Table 3]. There were no graft losses among our recipients. Graft survival was shown as Kaplan Meier curve [Figure 1], there was no statistical significance between both groups.{Table 1}{Table 2}{Table 3}{Figure 1}

 Discussion



Nonadherence to immunosuppressants is recognized to occur after renal transplantation. In a review of non-adherence, the cohort studies indicated that non-adherence contributes substantially to graft loss; a median (inter-quartile range) of 36% (14%:65%) of graft losses were associated with prior non-adherence. Meta-analysis of these studies showed that the odds of graft failure increased seven-fold (95% confidence interval, 4%:12%) in nonadherent subjects compared with adherent subjects.[7] Cross-sectional studies (n = 15) tended to rely on self-report questionnaires; however, these were poorly described; a median (interquartile range) of 22% (18%:26%) of recipients were non-adherent. In addition, a randomized controlled trial showed that after 6 months of randomization, 81.5% of the once-daily group and 71.9% of the twice-daily group remained persistent with the treatment (P = 0.0824). Among patients who remained engaged with the regimen, 88.2% of the once-daily group and 78.8% of the twice-daily group (P = 0.009) utilized the prescribed number of daily doses. When the patients received the twice-daily regimen, the average percentage of missed doses was 11.7% in the morning and 14.2% in the evening (P = 0.03).[8] They recommended that standardized methods of assessing adherence in clinical populations need to be developed, and future studies should attempt to identify the level of adherence that increases the risk of graft failure. However, this review showed nonadherence to be common and to have a large impact on transplant survival. That review, therefore, concluded significant improvements in graft survival could be expected from effective interventions to improve adherence.[8]

Despite a lack of studies involving drug interactions with once-daily tacrolimus, it is reasonable to believe that once-and twice-daily tacrolimus would exhibit similar drug interaction patterns as they share the same active constituent.[9] Once-daily tacrolimus clearly has potential benefits in clinical transplantation regarding simplifying immuno-suppressive regimens, improving medication compliance, decreasing pharmacokinetic variability, and consequently, reducing the risk of acute rejection, so once-daily formulation of tacrolimus is a step forward in kidney trans-plantation.[10] As it becomes more frequently utilized in clinical practice, more studies on efficacy, compliance, and safety with long-term use need to be conducted to better understand drug effects and refine drug administration among transplant patients.[5] Hence, in our study, once-daily formula of tacrolimus, (Advagraf), 33 patients were used and tested in comparison to the traditional twice-daily form (Prograf), 66 patients received live renal transplants. One year after the transplant, the renal function, post-transplant complications were comparable in both groups. In addition, similar to our results, Srinivas et al confirmed noninferiority of Advagraf in comparison to Prograf regarding to rejection episodes.[11] The incidence of diabetes and hypertension were comparable among the two groups by Albano et al showed that once-daily tacrolimus 0.2 mg/kg/day without induction therapy had similar efficacy to twice-daily tacrolimus 0.2 mg/kg/day.[12] The efficacy and safety of once a day Tacrolimus was maintained for four years in kidney, liver, and heart transplant recipients. Therefore, this formulation offers a convenient alternative to twice a day tacrolimus.[13]

The availability of once-daily tacrolimus formulation could thus offer the potential benefit of improved medication adherence and better allograft outcomes by decreasing pill burden and thereby simplifying dosing schedule, and noninferior if not superior, to twice-daily tacrolimus regarding safety and efficacy. Although being nonsignificant, a trend for better kidney function was present in this short-term study, so, long-term follow-up is needed to verify this.

Conflict of interest: None declared.

References

1Kaplan B, Srinivas TR, Meier-Kriesche HU. Factors associated with long-term renal allo-graft survival. Ther Drug Monit 2002;24:36-9.
2van Boekel GA, Kerkhofs CH, Hilbrands LB. Treatment satisfaction in renal transplant patients taking tacrolimus once daily. Clin Ther 2013;35:1821-90.
3United States Organ Transplantation. OPTN/ SRTR 2012 Annual Data Report. US Department of Health and Human Services; 2014. Available from: http://www.srtr.transplant.hrsa.gov/annual_reports/2012/flash/2012_SRTR_A DR/index.html. [Last accessed on 2014 June 06].
4Ho ET, Wong G, Craig JC, Chapman JR. Once-daily extended-release versus twice-daily standard-release tacrolimus in kidney transplant recipients: A systematic review. Transplantation 2013;95:1120-8.
5Posadas Salas MA, Srinivas TR. Update on the clinical utility of once-daily tacrolimus in the management of transplantation. Drug Des Devel Ther 2014;8:1183-94.
6Mengel M, Sis B, Haas M, et al. Banff 2011 Meeting report: New concepts in antibody-mediated rejection. Am J Transplant 2012; 12:563-70.
7Kuypers DR, Peeters PC, Sennesael JJ, et al. Improved adherence to tacrolimus once-daily formulation in renal recipients: A randomized controlled trial using electronic monitoring. Transplantation 2013;95:333-40.
8Butler JA, Roderick P, Mullee M, Mason JC, Peveler RC. Frequency and impact of nonadherence to immunosuppressants after renal transplantation: A systematic review. Transplantation 2004;77:769-76.
9Barraclough KA, Isbel NM, Johnson DW, Campbell SB, Staatz CE. Once-versus twice-daily tacrolimus: Are the formulations truly equivalent? Drugs 2011;71:1561-77.
10Hougardy JM, de Jonge H, Kuypers D, Abramowicz D. The once-daily formulation of tacrolimus: A step forward in kidney transplantation? Transplantation 2012;93:241-3.
11Srinivas TR, Kaplan B, Meier-Kriesche HU. The noninferiority trial: Don’t don’t do it. Am J Transplant 2010;10:2571-3.
12Albano L, Banas B, Klempnauer JL, et al. OSAKA trial: A randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation. Transplantation 2013;96:897-903.
13van Hooff JP, Alloway RR, Trunečka P, Mourad M. Four-year experience with tacro-limus once-daily prolonged release in patients from phase II conversion and de novo kidney, liver, and heart studies. Clin Transplant 2011; 25:E1-12.