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      Comparison of the long-term efficacy and safety of generic tacrolimus, Tacrobell, with Prograf in liver transplant recipients

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          The purpose of this study was to compare the safety and efficacy of generic tacrolimus (Tacrobell [TCB]) and a reference tacrolimus (Prograf [PGF]) in liver transplant recipients.

          Patients and methods

          We retrospectively analyzed 167 patients who used TCB or PGF between January 2009 and March 2016 for >1 year (TCB group, n=86; PGF group, n=81). To assess the efficacy and safety of TCB, we evaluated the relationship between drug dose and trough level, survival, rejection, infection, kidney function, and side effects.


          There was no difference in the preoperative demographics between the two groups. Moreover, there was no difference in the drug dose and trough level between the groups at 1 week after surgery. Coefficient of variation (CV) values were obtained at the drug trough level for each patient and no differences in CV values were identified within 1 year ( p=0.587) and up to 5 years ( p=0.824) in both groups. Rehospitalization ( p=0.1) and total rejection ( p=0.915) did not differ between the two groups, but the rejection severity, recorded as the rejection activity index value, was worse in the PGF group ( p=0.039). No difference was found in the infection rate ( p=0.818), and with regard to nephrotoxicity, there was no difference in the rate of patients with chronic kidney disease stage 3 and above during the follow-up period. No differences were found between the two groups in terms of drug side effects and adverse events.


          The generic tacrolimus, TCB, is a comparable alternative to the original tacrolimus, PGF, as a main immunosuppressive drug for liver transplantation.

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          Most cited references 13

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          High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation.

          We hypothesized that a high within-patient variability in clearance of tacrolimus and mycophenolate mofetil (MMF) would put patients at risk for periods of over- or underimmunosuppression and would thus lead to long-term chronic allograft nephropathy and graft loss after transplantation. From 297 patients transplanted between 1 January 2000 and 31 December 2004, the within-patient variability in clearance was calculated from tacrolimus whole-blood concentrations and mycophenolic acid (MPA) plasma concentrations drawn between 6 and 12 months post-transplantation. As a primary outcome, a composite end point consisting of graft loss, biopsy-proven chronic allograft nephropathy and 'doubling in plasma creatinine concentration in the period between t = 12 months post-transplantation and last follow-up' was used. In the study population of 297 patients, 34 patients reached the primary end point of graft failure. The within-patient variability in the clearance of tacrolimus and three other covariates are significant risk factors for reaching the composite end point of failure [P-values for intraindividual tacrolimus variability = 0.003, biopsy-proven acute rejection (BPAR) = 0.003, recipient age at transplantation = 0.005]. The mean tacrolimus concentration for controls [7.4 (+/- 2.9) ng/mL] and for failures [6.9 (+/- 2.5) ng/mL] was similar. Within-patient variability in the clearance of MPA was not related to reaching the composite end point of failure. This study shows a significant relationship between the high within-patient variability in the clearance of tacrolimus, but not for MPA, and long-term graft failure.
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            Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure.

            Wide variations in tacrolimus levels have been identified as a risk factor for inferior kidney allograft survival but past studies have not properly accounted for the dynamic nature of drug exposure over time. Here we evaluated whether time-varying exposure to tacrolimus increases the risk of long-term adverse outcomes in a retrospective cohort study in adult kidney transplant recipients on tacrolimus-based immunosuppression. Time-dependent Cox proportional hazards models were used to examine the association between the standard deviation of tacrolimus levels (TacSD) starting at 1-year post-transplant and the composite end point of late allograft rejection, transplant glomerulopathy, or total graft loss (including death). Among 356 patients, there was a significant 27% increase in the adjusted hazard of the composite end point for every 1-unit increase in TacSD (hazard ratio 1.27 (95% confidence interval 1.03, 1.56)). There was also a graded increase in the relative hazard for the composite end point by TacSD threshold (hazard ratios 1.33, 1.50, 1.84, and 2.56 for TacSD 1.5, 2, 2.5, and 3, respectively). The results were similar for total graft loss and the composite end point excluding death. Thus, increased time-dependent TacSD may be an independent risk factor for adverse kidney transplant outcomes. TacSD may serve as a monitoring tool to identify high-risk patients. Whether interventions to decrease TacSD will improve outcomes requires further study.
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              Generic immunosuppression in solid organ transplantation: a Canadian perspective.

              The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                13 February 2018
                : 12
                : 295-301
                Department of Surgery, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
                Author notes
                Correspondence: Dong Goo Kim, Division of Hepatobiliary-Pancreas Surgery and Liver Transplantation, Department of Surgery, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea, Tel +82 2 2258 6102, Fax +82 2 595 2992, Email kimdg@ 123456catholic.ac.kr
                © 2018 Choi et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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