0
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Update on the clinical utility of once-daily tacrolimus in the management of transplantation

      Drug Design, Development and Therapy

      Dove Medical Press

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Dear editor The review by Posadas Salas and Srinivas of the clinical utility of once-daily tacrolimus formulations in the management of transplant patients1 was timely and relevant. It is worth noting, however, the data were presented in a way that overlooked several key differences between two distinct once-daily tacrolimus formulations. These formulations differ in bioavailability, Cmax, Tmax, dose required to achieve target trough levels, and time to reach target trough. The specific formulation and dosing information of one product was detailed in this review (described as modified release 4 [MR-4]; Astagraf®, Astellas Pharma Inc., Tokyo, Japan), but no formulation or dosing details were provided for a very different once-daily tacrolimus formulation (LCP-Tacro™; Veloxis Pharmaceuticals A/S, Hørsholm, Denmark) for which a thorough review was recently published.2 The latter product is currently approved in Europe and under review by the US Food and Drug Administration in the US. In presenting data in this review, the authors did not identify which product was investigated in each of the studies discussed. This could easily lead to misinterpretation of results or erroneous conclusions, ie, that both once-daily formulations are the same. In fact, a careful parsing of the data clearly demonstrates that they are not equivalent. Misunderstanding of this point could have a potentially serious impact on appropriate dosing, safety, and patient management in the post-transplant setting. Differentiation between the two products is needed to clarify what appear to be conflicting results of the studies presented in this review. LCP-Tacro To date, two Phase III non-inferiority studies have been published evaluating the efficacy of LCP-Tacro in kidney transplant recipients.3,4 The first was an open-label, randomized trial evaluating conversion from twice-daily to once-daily LCP-Tacro in stable kidney transplant recipients and was detailed thoroughly by Posadas Salas and Srinivas.3 The second, a double-blind, double-dummy, randomized, non-inferiority trial of LCP-Tacro versus twice-daily tacrolimus in 543 de novo kidney transplant recipients, was not included in this review.4 The results of the 324-patient conversion trial and 543-patient de novo trial each individually demonstrated non-inferiority of once-daily LCP-Tacro to twice-daily tacrolimus with identical or lower rates of treatment failure.3,4 These trial results stand in direct opposition to data from trials that evaluated the alternative once-daily formulation (MR-4) in which rates of biopsy-proven acute rejection (BPAR), or treated rejection, were increased, in some cases significantly so.5–7 In one of these studies, the MR-4 formulation of once-daily tacrolimus failed to demonstrate non-inferiority.5 Posadas Salas and Srinivas report results of a study that demonstrated rejection episodes requiring anti-lymphocyte therapy were more commonly seen among de novo kidney transplant patients treated with the MR-4 once-daily formulation of tacrolimus compared to twice-daily tacrolimus. They go on to note that about one-third of patients who received MR-4 had trough levels below target during the early post-transplant period (day 3 post-transplant). While the difference in rejection rate did not reach statistical significance, the authors note a trend toward higher mean tacrolimus levels in the twice-daily tacrolimus group who did not experience BPAR compared to those who developed BPAR. These data stand in contrast to data not presented by Posadas Salas and Srinivas, which demonstrate that in de novo kidney transplant patients treated with the LCP-Tacro once-daily formulation, therapeutic tacrolimus concentrations were achieved rapidly – with 66.5% of patients having a serum tacrolimus trough concentration of at least 6 ng/mL 24 hours after their first dose of LCP-Tacro.8 LCP-Tacro-treated patients in this study experienced similar, though numerically lower, rates of BPAR compared to twice-daily tacrolimus at both 1 year and 2 years post-transplant. Furthermore, pharmacokinetic (PK) differences are noteworthy between the two once-daily tacrolimus formulations. In contrast to data demonstrating the need for potentially higher total daily doses of tacrolimus when the MR-4 formulation is used,5,9 LCP-Tacro has consistently demonstrated greater bioavailability and significantly lower total daily dose requirements compared with twice-daily tacrolimus (Prograf®, Astellas Pharma Inc.) in kidney and liver recipients and in both the de novo and conversion settings.8,10–12 The Phase II study of 47 stable kidney transplant patients cited by Posadas Salas and Srinivas, reporting a 30% lower daily dosing requirement, evaluated the PK of LCP-Tacro after conversion from twice-daily tacrolimus,11 and cannot be extrapolated to the MR-4 formulation.10 Results of this study, as summarized in the review, were that patients taking LCP-Tacro had similar overall tacrolimus exposure (area under the curve) but with significantly lower Cmax (P,0.0001), delayed Tmax (1.8 hours for twice-daily versus 6 hours for LCP-Tacro, P=0.0001), lower peak-trough ratios (P<0.0001 on day 14, P=0.0004 on day 21), and less fluctuation (P<0.0001) compared with twice-daily tacrolimus.10 Based on the PK data presented in this response, the greater bioavailability and lower dose requirement are clinically relevant PK differences of the LCP-Tacro formulation compared with MR-4. The authors put forth the message that the PK profiles of once- and twice-daily tacrolimus suggest bioequivalence, yet available data for LCP-Tacro do not support this claim versus twice-daily or the MR-4 once-daily tacrolimus formulations. While no direct Phase III data comparing the two once-daily formulations have been published, Phase I data in healthy volunteers demonstrate that LCP-Tacro was 50% more orally bioavailable compared to the MR-4 once-daily formulation.13 This difference could result in significantly different dose requirements and conversion factors, and it is vital for clinicians to understand these important differences to ensure safe use of these unique once-daily formulations of tacrolimus. Conclusion Without clarity on the specific once-daily tacrolimus formulation evaluated in each of the trials discussed in the review by Posadas Salas and Srinivas, it is difficult to reconcile potentially conflicting data. A more complete review of the data regarding once-daily formulations clearly shows important differences between the MR-4 and LCP-Tacro once-daily tacrolimus formulations. These differences may have important clinical implications when selecting a once-daily tacrolimus to manage immunosuppression in transplant recipients.

          Related collections

          Most cited references 10

          • Record: found
          • Abstract: found
          • Article: not found

          Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study.

          This multicenter, 1:1-randomized, parallel-group, noninferiority study compared the efficacy and safety of twice-daily tacrolimus (Tacrolimus BID; Prograf) and once-daily tacrolimus prolonged release (Tacrolimus QD; Advagraf), combined with steroids and low-dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. A double-blind, double-dummy 24-week period was followed by an open extension of up to 12 months posttransplant. Biopsy-proven acute rejection rate at 24 weeks (primary endpoint, per-protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval-1.8%, 10.9%, just outside the prespecified 10% noninferiority margin). Kaplan-Meier 12-month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. Both treatment groups showed equally well-maintained renal function at 12 months (mean creatinine clearance approximately 67 mL/min) and similar adverse event profiles. Overall results obtained with either Tacrolimus QD or BID, without antibody induction, were good, supporting use of the once-daily formulation as an effective alternative to the established twice-daily formulation. ©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients.

            Once-daily tacrolimus extended-release formulation (Prograf XL, formerly referred to as MR or MR4) was compared with the twice-a-day tacrolimus formulation (TAC) and cyclosporine microemulsion (CsA), all administered in combination with mycophenolate mofetil (MMF), corticosteroids and basiliximab induction, in a phase 3, randomized (1:1:1), open-label trial in 638 de novo kidney transplant recipients. In combination with MMF and corticosteroids, XL had an efficacy profile comparable to TAC and CsA. XL/MMF and TAC/MMF were statistically noninferior at 1-year posttransplantation to CsA/MMF for the primary efficacy endpoint, efficacy failure (death, graft loss, biopsy-confirmed acute rejection (BCAR) or lost to follow-up). One-year patient and graft survival were 98.6% and 96.7% in the XL/MMF group, 95.7% and 92.9% in TAC/MMF group and 97.6% and 95.7% in CsA/MMF group. The safety profile of XL in comparison with CsA was similar to that observed with TAC in this study and consistent with previously published reports of TAC in comparison with CsA. The results support the safety and efficacy of tacrolimus in combination with MMF, corticosteroids and basiliximab induction, as well as XL as a safe and effective once-daily dosing alternative.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Once- versus twice-daily tacrolimus: are the formulations truly equivalent?

              Tacrolimus is a cornerstone immunosuppressant agent in the prevention of organ rejection following transplantation. While typically administered twice daily (Prograf®), a modified-release once-daily formulation (Advagraf®) has recently been developed and licensed for use. To date, the majority of published data relating to the use of Advagraf® have arisen from industry-sponsored clinical trials. These have shown that conversion from Prograf® to Advagraf® on a 1 mg : 1 mg basis in both stable and de novo kidney and liver transplant recipients yields lower peak concentrations (C(max)) but equivalent overall drug exposure (area under the concentration-time curve from 0 to 24 hours post-dose; AUC(24)) and trough concentrations (C(min)). This has led to the proposal that the same total daily dose, target C(min) and therapeutic drug monitoring (TDM) strategies can be applied irrespective of preparation. However, while Advagraf® fulfils criteria for bioequivalence according to the European Medicines Agency and US FDA, lower tacrolimus exposure has been observed in the majority of clinical studies, particularly in the early post-transplant period. This has resulted in a need for higher doses of Advagraf® compared with Prograf® to achieve similar C(min) values. Significant between-subject variability in the C(min)/AUC(24) relationship with Advagraf® has also been demonstrated, suggesting possible problems with TDM based on C(min) values. In non-comparative conversion studies, Advagraf® demonstrated similar efficacy and safety to Prograf®. However, phase III studies in de novo kidney and liver transplant recipients have shown higher rates of acute rejection with Advagraf®, possibly explained by the differing C(max) values achieved with the two preparations. While it has been suggested that once-daily administration may improve compliance, no studies have proven this to be the case. This article reviews the pharmacokinetics, efficacy, adverse effects and utility of Advagraf® in relation to its equivalence to Prograf®, and areas that require additional research are identified.
                Bookmark

                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                07 May 2015
                : 9
                : 2581-2584
                Affiliations
                Department of Pharmacy, Jackson Memorial Hospital, University of Miami Leonard M Miller School of Medicine Miami, FL, USA
                Division of Nephrology and Hypertension, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
                Author notes
                Correspondence: Jane Revollo, Jackson Memorial Hospital, Pharmacy Services, B-069, 1611 NW 12th Avenue Miami, FL 33136, USA, Email jane.revollo@ 123456jhsmiami.org
                Correspondence: Maria Aurora Posadas Salas, Division of Nephrology and Hypertension, Department of Medicine, 96 Jonathan Lucas Street, Charleston, SC 29425, USA, Tel +1 843 792 2123, Fax +1 843 792 8399, Email posadas@ 123456musc.edu
                Article
                dddt-9-2581
                10.2147/DDDT.S84301
                4428359
                26005334
                © 2015 Revollo. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Letter

                Pharmacology & Pharmaceutical medicine

                Comments

                Comment on this article