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Mounting Clinical Evidence With Tacrolimus Generic Products

Alloway, Rita R. PharmD1

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doi: 10.1097/TP.0000000000001892
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Although the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Currently, the United States Food and Drug Administration (FDA) average bioequivalence acceptance criterion for the area under the time concentration curve (AUC, exposure) and for the maximal concentration (Cmax) is 80% to 125% when comparing test with reference products. However, differing worldwide bioequivalence regulatory standards for narrow therapeutic index drugs make it difficult to interpret and compare bioequivalence study results.1-3 The European Medicines Agency requires a narrower 90.00% to 111.11% acceptance criterion for AUC but the usual 80.00% to 125.00% acceptance limits for Cmax for narrow therapeutic index drugs, tacrolimus.1 Health Canada has adopted similar standards as the European Medicines Agency, but has set the AUC acceptance range at 90.00% to 112.00%.2 The FDA has classified tacrolimus as a narrow therapeutic index drug and recommended using the scaled average bioequivalence approach to determine bioequivalence.3,4 Despite differing regulatory standards, several tacrolimus formulations are approved for patient use around the world.

Several professional transplant societies and publications have questioned the appropriateness of the standard bioequivalence approval process using 2-way cross-over studies in healthy volunteers and generated significant skepticism over the generic approval process.5-7 These concerns are threefold: (1) the pharmacokinetic (PK) properties of generic and brand products in healthy volunteers may not reflect those in transplant recipients, (2) bioequivalence between generic and brand may not ensure bioequivalence between generics, and (3) high-risk patients may have specific bioequivalence concerns.

Historically, lack of definitive clinical evidence with properly controlled trials in target populations generated the basis for these concerns. Limitations of previous studies include retrospective evaluations; case reports; inadequate study design (underpowered, without appropriate controls); analysis of trough concentrations only; lack of analysis of confounders, such as comedications and comorbidities; incorrect PK analysis; and use of nonspecific immunoassays to assess tacrolimus concentrations, thus leading to considerable bias and limited conclusions. Several single-center retrospective studies have been reported and are summarized in meta-analysis form.

These limitations may have resulted from lack of resources, because generic manufacturers do not typically fund clinical trials to test their formulation against the reference product or other generic products after approval. However, 2 generic tacrolimus manufacturers, Sandoz (US, UK, and Germany) and Chong Kun Dang Pharmaceutical (Seoul Korea), have funded prospective randomized studies of tacrolimus in both the conversion and de novo renal transplant settings. Additionally, the FDA has funded 3 large studies of generic tacrolimus in transplant recipients (NCT 01889758, NCT 02014103, NCT 02866682), and the results are currently pending. However, most of these studies are conversion studies with short follow-up, thus not allowing for assessment of long-term safety.

The work by Arns et al,8 in this issue of Transplantation and funded by Sandoz differs from other published investigations and contributes to our understanding of the efficacy and safety of tacrolimus in de novo kidney transplant recipients. The term “branded” tacrolimus in the title is not entirely accurate because generic tacrolimus products can also be branded. The tacrolimus generic product in this study is branded as Hexal. A more accurate description of Prograf is the “innovator” tacrolimus. This prospective multicenter parallel group, open-label study randomized de novo kidney transplant patients to receive generic tacrolimus (TacHexal, Sandoz, Germany) or reference tacrolimus (Prograf, Astellas, Japan). The initial design for phase 1 compared the exposure between different formulations (AUC0-12hr) in 60 evaluable patients with planned 12-hour PKs profiling on days 3, 10, and 30 posttransplant and 4-hour PK profiling at months 3 and 6. Phase 2 was designed to increase enrollment to 326 patients and demonstrate noninferiority of TacHexal compared with Prograf in terms of renal function, evaluated using the Nankivell equation, 6 months posttransplant. Unfortunately, the trial was not completed as designed due to patient unwillingness to undergo 12-hour PK assessments at days 10 and 30, and enrollment in phase 2 was halted. Eighty-one patients were enrolled, 73 were analyzed in the intention-to-treat population, and 51 completed the 6-month study. Approximately 20 patients in each treatment group underwent 12-hour PK evaluation on days 3, 10, and 30 in phase 1. There were no statistically significant differences between formulation during these time points for dose normalized AUC or Cmax. The phase 2 analysis of renal function included a variety of estimated glomerular filtration rate (eGFR) estimates. TacHexal was noninferior to Prograf for eGFR at 6 months as measured by the modified diet in renal disease and chronic kidney disease epidemiology collaboration equations. TacHexal was superior for eGFR at 6 months as measured by the Nankivell and Cockcroft-Gault equations. There were no statistically significant differences noted in biopsy-proven acute rejection (5.7% vs 7.9%), death-censored graft loss (0% vs 2.6%), or death (0% vs 2.6%) between TacHexal and Prograf, respectively. Adverse events were reported in 97.1% TacHexal and 100.0% Prograf-treated patients and were no different between groups.

The primary limitation of this study is the inability to complete planned recruitment due to lack of enrollment in the PK portion of this study. Although early posttransplant PK studies provide interesting data, it is difficult to associate a formulation effect with differences in PK parameters due to the variety of variables impacting tacrolimus exposure immediately after transplantation. These include a lack of steady state tacrolimus dosing, changes in concomitant interacting drugs, alterations in fluid status, and hemoglobin and dietary changes. Additionally, pharmacogenetic characterization of these patients could have added to the robustness of the observations; however, the patient population appeared to be racially homogenous and primarily male which may have limited genomic diversity in drug-transporting and metabolizing enzymes. In addition, tacrolimus levels were analyzed by local standards, therefore unlikely batched and analyzed by the criterion standard high-performance liquid chromatography mass spectrometry. There were no observed PK differences between formulations at the time points analyzed. This study does not test bioequivalence because bioequivalence studies must be conducted when the same subject receives the same dose of 2 different formulations, and the PK parameters are compared via confidence interval testing. Because this study is comparing 2 different groups of patients receiving tacrolimus, dose-normalized PK results are provided to allow PK comparisons between the 2 different subject groups. The statistical analysis performed compares PK parameters between the 2 groups, not bioequivalence.

Despite its limitations, this de novo transplant study adds value given its ability to compare the adverse event profile in renal transplant recipients receiving 2 tacrolimus formulations for up to 6 months posttransplant. Although adverse events were frequently reported, there were no observed differences by formulation. Renal function appeared to be superior as per the intention-to-treat analysis, a finding that must be interpreted cautiously given the under enrollment in the study.

This article provides data in de novo renal transplant recipients on the safety and efficacy of Sandoz generic tacrolimus at 6 months posttransplant when compared with the branded innovator formulation. These data and other previously published work relating to generic tacrolimus conversion in renal transplant patients challenges the clinicians' views and concerns with generic tacrolimus use. However, TacHexal is only one of many generic tacrolimus formulations and is manufactured by Sandoz, a company with a long history in transplantation. This study does not address the safety and efficacy of other tacrolimus formulations in renal transplantation or in other nonrenal solid organ transplant recipients. Because many knowledge gaps in this field still exist, public concerns will likely remain despite the significant market penetration of generic tacrolimus around the world. Although bioequivalence trials in healthy volunteers have proven to provide safe and effective generic formulations, other generic tacrolimus manufacturers should consider evaluating each tacrolimus formulation in the target population to continue to address public concern.


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2. Health Canada. Comparative bioavailability standards: formulations used for systemic effects. Published May 22, 2012. Accessed October 26, 2016.
3. Food and Drug Administration. Draft guidance on tacrolimus. < Published July 2014. Accessed December 2, 2015.
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7. van Gelder T. European society for organ Transplantation Advisory Committee recommendations on generic substitution of immunosuppressive drugs. Transpl Int. 2011;24:1135–1141.
8. Arns W, Huppertz A, Rath T, et al. Pharmacokinetics and clinical outcomes of generic tacrolimus (Hexal) versus branded tacrolimus in de novo kidney transplant patients: a multicenter randomized trial. Transplantation. 2017;101;2780–2788.
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