a-1year-comparison-of-generic-tacrolimus-tacni-and-prograf-in-renal-tr

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Volume 2 • Issue 1 • 1000113 J Clin Exp Transplant an open access journal Research Article Open Access Lindnér and Lindnér J Clin Exp Transplant 2017 2:1 Research Article OMICS International Journal of Clinical and Experimental Transplantation Journal of Clinical and Experimental Transplantation Corresponding author: Per Lindnér Transplant Institute Institute of Clinical Sciences Sahlgrenska Academy at University of Gothenburg Sahlgrenska University Hospital SE-413 45 Gothenburg Sweden Tel: +46313421000 E-mail: per.lindnersurgery.gu.se Received February 15 2017 Accepted May 15 2017 Published May 19 2017 Citation: Lindnér C Lindnér P 2017 A 1-year Comparison of Generic Tacrolimus Tacni ® and Prograf ® in Renal Transplant Patients: A Retrospective Matched Group Analysis. J Clin Exp Transplant 2: 113. Copyright: © 2017 Lindnér C et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use distribution and reproduction in any medium provided the original author and source are credited. A 1-year Comparison of Generic Tacrolimus Tacni ® and Prograf ® in Renal Transplant Patients: A Retrospective Matched Group Analysis Cecilia Lindnér 1 and Per Lindnér 2 1 Institute of Laboratory Medicine Lund University SE-221 85 Lund Sweden 2 Transplant Institute Institute of Clinical Sciences Sahlgrenska Academy at University of Gothenburg Sahlgrenska University Hospital SE-413 45 Gothenburg Sweden Abstract Introduction: The 1-year-outcome of adult patients treated with Tacni ® or Prograf ® following de novo renal transplantation including patient survival graft loss Biopsy Proven Acute Rejection BPAR and serious adverse events were compared. 186 patients who underwent their frst renal transplantation between 2011 and 2014 were included in a retrospective matched group analysis 91 patients treated with Tacni ® which were compared with a matched control group n95. Material and Methods: This was a retrospective study of two different time cohorts of patients who underwent kidney transplantation at Sahlgrenska University Hospital. Data was obtained from patient charts and from the local quality registry. Patients from the two groups were matched in a group matching fashion. The matching was based upon the patient’s age and gender age of the donor living/deceased donor and Cold Ischemia Time CIT. Results: The two groups were well matched for living donor transplants gender donor and recipient age. The combined endpoint of freedom from BPAR graft loss and death 12 months post-transplantation was 85 in the P-group and 86 in the T-group p0.90. There was one death in the T-group which was not related to the drug p1.00. Graft survival at 12 months was similar 99 in both groups p0.97. The BPAR at 12 months was 12 T and 14 P respectively p0.72. The measured GFR at 12 months was also similar 54.5 and 56.0 ml/min/1.73 m 2 p0.59. There were no signifcant differences in Tacrolimus levels. Conclusion: One year after transplantation generic Tacrolimus is no different to the original version. Both drugs show good effcacy the safety is comparable and the drug concentrations do not differ. Keywords: Renal transplantation Immunosuppression Tacrolimus Generic Introduction Corticosteroids and Calcineurin Inhibitors CNIs such as Tacrolimus and ciclosporin are the main molecules used in immunosuppressive renal transplantation protocols throughout the world. Following the expiration of the patent protection of Tacrolimus in 2009 several generic versions of the drug have entered the market. However with the increasing use of these generic immunosuppressants well designed studies comparing the original Tacrolimus Prograf® Astellas Pharma Inc. Tokyo Japan with generic Tacrolimus in order to ensure the long-term safety of the drug are required 1. The first bioequivalence of a generic Tacrolimus was demonstrated in the US in 20 healthy volunteers in 2009 and the drug was thereafter approved by the United States Federal Drug Administration. However due to the significant differences in drug metabolism between healthy volunteers and transplant patients many suggest that meeting the criteria of bioequivalence in healthy individuals is insufficient to ensure the safety and efficacy of generic substitutions of Narrow Therapeutic Index NTI drugs such as Tacrolimus 23. In addition a recent study showed that Tacni® Teva UK did not meet the bioequivalence criteria in elderly transplant patients and that the use of Tacni® resulted in a significantly higher systemic drug exposure. In the long run this may put the patients at higher risk of Calcineurin Inhibitor-Related Toxicity CIRT and impaired long-term outcomes 2. The trough concentrations and dose requirements of generic Tacrolimus are shown to be comparable to brand-name Tacrolimus by several studies performed in the past few years 4-7. Nevertheless dose titration is often required after the switch from the reference drug to generic Tacrolimus and close therapeutic drug monitoring is needed in order to achieve a satisfactory balance between maximizing efficacy and minimizing dose-related toxicity. Due to the cost-saving benefits and the overall evidence from several studies suggesting that generic Tacrolimus appears safe switching from brand-name Tacrolimus is widely encouraged. However the follow-up period in these studies was brief maximum nine months and there was no observation of the long-term outcome of patients 4-7. In addition there are only two studies to date that have studied patients who were treated with generic Tacrolimus on the day of discharge after renal transplantation as opposed to being switched from reference Tacrolimus 23. Considering this together with the concerns about bioequivalence in elderly patients data showing comparable clinical effectiveness of generic and brand-name Tacrolimus are needed 1. Te primary aim of the study was to investigate potential diferences regarding the overall safety and efcacy of generic versus original Tacrolimus during the frst year afer transplantation.

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Page 2 of 5 Citation: Lindnér C Lindnér P 2017 A 1-year Comparison of Generic Tacrolimus Tacni ® and Prograf ® in Renal Transplant Patients: A Retrospective Matched Group Analysis. J Clin Exp Transplant 2: 113. Volume 2 • Issue 1 • 1000113 J Clin Exp Transplant an open access journal Materials and Methods Study design Tis was a retrospective non-powered study of two diferent time cohorts of patients who underwent kidney transplantation at Sahlgrenska University Hospital SU. Data was obtained from patient charts and from TIGER the local quality registry. Sample size was based on utilizing all renal transplant patients on Tacni® comparing them with a matched group of patients treated with Prograf® on day of discharge. Patients from the two groups were matched in a group matching fashion. Te matching was based upon the patient’s age and gender age of the donor living/deceased donor and Cold Ischemia Time CIT. Te closest matches were applied to living vs. deceased donors. Second closest matching was applied to age and CIT which were kept within two years and three hours respectively. Te primary objective of the study was to investigate the combined endpoint of freedom from Biopsy Proven Acute Rejection BPAR graf loss and death 1 year afer transplantation in a population treated with generic Tacrolimus compared with a population treated with Prograf®. Secondary objectives were to compare the following parameters afer 1 year: • Graf survival. • BPAR at 6 and 12 months. • Calculated glomerular fltration rate eGFR according to the MDRD equation and. • Measured GFR if available. • Serious adverse events at 6 and 12 months. • Tacrolimus levels at post-operative day 4 7 14 and 21. Patients Adult patients 18+ years receiving a frst single kidney transplant from a deceased or living donor who were treated with Tacni® or Prograf® on day of discharge were enrolled. Exclusion criteria included multi-organ transplants or previous renal or non-renal transplants patients under 18 years of age as well as patients transplanted before the year of 2011. A total of 622 patients were screened using the local registry at Transplantationszentrum TIGER at SU. 91 patients on Tacni® met the eligibility criteria and were enrolled in the study. 169 Prograf® patients were identifed from this group 95 were selected from the matching process Figure 1. In total 186 patients could be included in the study. Immunosuppression Standard immunosuppressive regimen consisted of Tacrolimus mycophenolate mofetil and steroids. Induction therapy was given with two doses of Basiliximab. According to the center transplant protocol Tacrolimus was initiated the day afer transplantation at a dose of 0.05 mg/kg twice daily aiming at a target level of 5-9 ng/ml during the frst Pat ents treated with Tacni ® n91 n622 inclusion criteria n362 Allocated to matching n260 Pat ents treated with Tacni ® n91 Pat ents treated with Prograf ® Pat ents treated with Prograf ® n95 Excluded in the matching process n74 Excluded not mee t ng Figure 1: A CONSORT diagram.

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Page 3 of 5 Citation: Lindnér C Lindnér P 2017 A 1-year Comparison of Generic Tacrolimus Tacni ® and Prograf ® in Renal Transplant Patients: A Retrospective Matched Group Analysis. J Clin Exp Transplant 2: 113. Volume 2 • Issue 1 • 1000113 J Clin Exp Transplant an open access journal 3 months. MMF was initiated in a dose of 1 g twice daily. Prednisolon was initiated at a dose of 50 mg twice daily with a weaning to 10 mg daily at 1 month and 5 mg daily at three months. Statistical analysis Te matching process was conducted utilizing population matching by minimizing t-values based on living/deceased donor donor age recipient age and CIT. Statistical analysis was carried out to compare preoperative patient characteristics perioperative primary outcomes and complications using the Chi-square test Fisher’s Exact test for dichotomous variables and the Mann-Whitney U-test for continuous variables. Te study was approved by the Regional Ethics Committee in Gothenburg Dnr: 475-15. Results Te primary aim of the study was to investigate potential diferences regarding the overall safety and efcacy of generic versus original Tacrolimus more specifcally to compare the 1-year-outcome of adult patients treated with Tacni® or Prograf® following de novo renal transplantation. Te baseline characteristics of the study population are shown in Table 1. Te study groups were well matched for living/deceased donor donor age recipient age and CIT. Te combined endpoint of freedom from patient death graf loss or rejection which was the primary endpoint of the study showed no diference between the two groups. 85.3 of Prograf® patients and 85.7 of Tacni® p0.90 patients were free of complications within one year of transplantation including death graf loss or rejection Table 2. Out of the 186 subjects that were included in the study only one death was recorded due to postoperative bleeding in a patient treated with Tacni® Table 2. Te cause of death was not related to the choice of immunosuppression. One subject in each group experienced graf loss Table 2. BPAR was recorded in 24 12.3 of the 186 subjects. 13 13.7 and 11 12.1 patients experienced BPAR in the Prograf® and Tacni® group respectively p0.72 Table 2. Variable Prograf ® n95 Tacni ® n91 p-value Age 53.8 22.4- 74.5 52.321.1-73.0 0.84 Sex - - 0.48 Male 54 56.8 46 50.5 - Female 41 43.2 45 49.5 - Race for eGFR -p - 1.00 Black 0 0.0 0 0.0 - Other 95 100.0 91 100.0 - Donor living or deceased - - 1.00 Living 37 38.9 35 38.5 - Deceased 58 61.1 56 61.5 - Donor age years 55.0 11.0-74.0 53.0 7.0-80.0 0.50 Table 1: Demographics and baseline characteristics. For categorical variables n is presented and for continuous variables median min-max. Chi-square test and Fishers Exact test was applied for dichotomous variables and Mann-Whitney U-test for continuous variables. Variable Prograf ® n95 Tacni ® n91 p-value Age 53.8 22.4- 74.5 52.321.1-73.0 0.84 Sex - - 0.48 Male 54 56.8 46 50.5 - Female 41 43.2 45 49.5 - Race for eGFR - - 1 Black 0 0.0 0 0.0 - Other 95 100.0 91 100.0 - Donor living or deceased - - 1 Living 37 38.9 35 38.5 - Deceased 58 61.1 56 61.5 - Donor age years: 55.0 11.0-74.0 53.0 7.0-80.0 0.5 Table 2: Comparison of renal function and survival. For categorical variables n is presented and for continuous variables median min-max Chi-square test and Fishers Exact test was applied for dichotomous variables and Mann-Whitney U-test for continuous variables. Variable Prograf ® n95 Tacni ® n91 At 12 months At 12 months Subjects with SAE n 41 43.2 43 47.3 Total number of SAE 85 75 Rejection 14 14 Kidney disease 3 6 UTI 7 4 Other infection 16 9 Bleeding 2 4 Lymphocele 6 0 Tumor 3 4 Cardiovascular disease 5 2 Other 8 12 Neutropenia 2 0 Sepsis 13 11 Uretary complications 4 7 Diabetes 0 2 Table 3: Serious adverse events: Any recorded event requiring or prolonging hospital stay post-transplantation. Te measured GFR mGFR at 12 months was available in 79 patients 83 in the Prograf® group and 75 patients 82 in the Tacni® group Table 2. mGFR was measured using iohexol-clearance. Te median value of mGFR was 56.0 22.0-103.0 and 56.0 7.0- 91.0 mL/min/1.73 m 2 for Prograf® and Tacni® respectively p0.59. eGFR at 12 months was calculated according to the MDRD-formula. S-creatinine levels at 12 months were available in 90 Prograf® and 89 Tacni® patients. Te median value of eGFR was estimated to 59.4 21.5- 127.5 mL/min/1.73 m 2 for Prograf® and 59.7 4.8-122.8 mL/min/1.73 m 2 for Tacni® p0.45 so no signifcant diference in renal function was observed between the groups according to both mGFR and eGFR. Serious adverse events were defned according to European Medicines Agency guidance. Te events were grouped into 13 categories Table 3. As demonstrated in the table there was no diference in the number of SAE between the groups. Tacrolimus levels increased over time and stabilized between 14 and 21 days at a level between 8 and 9 ng/ml Figure 2. Tere was no

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Page 4 of 5 Citation: Lindnér C Lindnér P 2017 A 1-year Comparison of Generic Tacrolimus Tacni ® and Prograf ® in Renal Transplant Patients: A Retrospective Matched Group Analysis. J Clin Exp Transplant 2: 113. Volume 2 • Issue 1 • 1000113 J Clin Exp Transplant an open access journal signifcant diference in mean value and standard deviation between the two groups. Te accumulated doses of Tacrolimus were not measured in the study. Discussion and Conclusion Te use of generic immunosuppressive drugs in transplantation is a controversial topic. Tere is a consensus among transplant societies that clinical data is lacking and that caution should be exercised 8. Te reluctance to use generic drugs such as Tacni® in organ transplantation is partly related to the fact that most are NTI drugs sometimes called “critical dose drugs” and that either low dosing or overdosing could have serious consequences for both patients and society 9. Another controversy is whether a demonstration of bioequivalence by a single fxed dose study in healthy adults can ofer a sufcient guarantee of therapeutic equivalence in solid organ transplant patients 10. A number of groups have shown acceptable short-term outcomes with generic Tacrolimus formulations in non-randomized clinical studies in de novo kidney transplant recipients. Most of these were conversion studies and compared Prograf® to the generic formulations Tacrobell® and Pan Graf® 41112. In one of the two published de novo studies Adoport® was compared with Prograf® 13. Tere were no diferences in 6-month outcomes regarding clinical results histology in protocol biopsies and formation of donor specifc antibodies. In the other de novo study 3 focusing on pharmacokinetics in 117 patients efcacy and safety data were comparable over the 9-month study period. Tere is only one study comparing Tacni to Prograf® 3 which noticed a higher drug exposure with Tacni® in elderly patients. To the best of our knowledge our current study is the largest to evaluate de novo use of generic Tacrolimus and the frst study comparing the 1-year outcomes of Tacni®. Te aim of the study was to investigate potential diferences regarding the overall safety and efcacy. When designing the study we wanted to create as large a sample size as possible to increase the statistical power. Te limiting factor was that Tacni® has only been part of the standard immunosuppression regimen at our institution for three years and therefore the number of kidney transplant patients on Tacni® was restricted to approximately 100 patients. Since Prograf® was the only Tacrolimus drug on the market for many years we had a larger pool of patients to choose from when selecting our control group. For this reason we closely matched the control group with the Tacni® group based on gender living/deceased donor donor age recipient age and CIT. By matching by group rather than in a 1:1 ratio we were able to make the groups more closely correlated to one another thus eliminating the most evident confounders and increased the strength of the result. Except for the Tacrolimus brand the immunosuppressive protocol was identical in the two groups. Even if we cannot exclude any potential diferences in bioavailability in a subgroup of patients we did not see any evidence of this and overall the one-year efcacy and safety of renal transplantation with Tacni® was not diferent compared to Prograf®. Interchangeability between generic Tacrolimus and Prograf® is an important issue in solid organ transplantation for health economic reasons. Te switch in protocol at our institution from Prograf® to Tacni® in 2013 resulted in signifcant savings as Tacni® was approximately 40 cheaper than reference Tacrolimus in Sweden. In general generic medicines are typically 20 to 90 cheaper than originator equivalents. For example in 2010 alone the use of generics in the American health system saved 158 billion an average of 3 billion every week and a study by the Generic Pharmaceutical Association GPhA showed that prescribing of generic products saved the US economy 931 billion between 2001 and 2010 14. Compared to most other studies this is one of the few which analyses data of patients who were treated with generic Tacrolimus on the day of discharge following renal transplantation as opposed to being switched from reference Tacrolimus 23. More data supporting the use of generic Tacrolimus will be generated from transplant registries which can provide evidence about long-term graf survival in larger patient cohorts. Te absence of evidence of diferences is not equal to evidence of no diferences 8 but still the results obtained in this study supports Figure 2: Mean trough tacrolimus levels during the frst month after transplantation. Bars represents a 95 confdence interval.

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Page 5 of 5 Citation: Lindnér C Lindnér P 2017 A 1-year Comparison of Generic Tacrolimus Tacni ® and Prograf ® in Renal Transplant Patients: A Retrospective Matched Group Analysis. J Clin Exp Transplant 2: 113. Volume 2 • Issue 1 • 1000113 J Clin Exp Transplant an open access journal that the use of generic Tacrolimus is a safe method to improve health economy in transplantation. In conclusion in this study one-year post-transplantation immunosuppression with generic Tacrolimus Tacni® is not diferent from medication with the original version. Both drugs show good efcacy the safety is comparable and the drug concentrations do not difer. References 1. Molnar A Fergusson D Tsampelieros A Bennett A Fergusson N et al. 2015 Generic immunosuppression in solid organ transplantation: systematic review and metaanalysis. BMJ 350: 3163. 2. Robertsen I Asberg A Ingero AO Vethe NT Bremer S et al. 2015 Use of generic tacrolimus in elderly renal transplant recipients: precaution is needed. Transplantation 99: 528-532. 3. Min SI Ha J Kim YS Ahn SH Park T et al. 2013 Therapeutic equivalence and pharmacokinetics of generic tacrolimus formulation in de novo kidney transplantations. Nephrol Dial Transplant 28: 3110. 4. McDevitt-Potter LM Sadaka B Tichy EM Rogers CC Gabardi S 2011 A multicentre experience with generic tacrolimus conversion. Transplantation 92: 653. 5. Rosenborg S Nordström A Almquist T Wennberg L Bárány P 2014 Systematic conversion to generic tacrolimus in stable kidney transplant patients. Clin Kidney J 7: 151-155. 6. Spence MM Nguyen LM Hui RL Chan J 2012 Evaluation of clinical and safety outcomes associated with conversion from brand‐name to generic Tacrolimus in transplant recipients enrolled in an integrated health care system. Pharmacotherapy: Pharmacotherapy 32: 981-987. 7. Momper JD Ridenour TA Schonder KS Shapiro R Humar A et al. 2011 The impact of conversion from prograf to generic tacrolimus in liver and kidney transplant recipients with stable graft function. Am J Transplant 11: 1861-1867. 8. Gelder TV 2011 European society for organ transplantation advisory committee recommendations on generic substitution of immunosuppressive drugs. Transpl Int 24: 1135-1141. 9. Allard J Fortin MC 2014 Is it ethical to prescribe generic immunosuppressive drugs to renaltransplant patients Can J Kidney Health Dis 1: 23. 10. Harrison JJ Schiff JR Coursol CJ Daley CJ Dipchand AI et al. 2012 Generic immunosuppression in solid organ transplantation: a Canadian perspective. Transplantation 93: 657-665. 11. Kim SJ Huh KH Han DJ Moon IS Kim SJ et al. 2009 A 6-month multicenter single-arm pilot study to evaluate the effcacy and safety of generic tacrolimus TacroBell after primary renal transplantation. Transplant Proc 41: 1671-1674. 12. Guleria S Kamboj M Chatterjee A Sharma M Awasthy V et al. 2008 Generic tacrolimus Pan Graf in renal transplantation: an experience of 155 recipients in India. Transplant Proc 40: 2237-2239. 13. Melilli E Crespo E Sandoval D Manonelles A Sala N et al. 2015 De novo use of a generic formulation of tacrolimus versus reference tacrolimus in kidney transplantation: evaluation of the clinical results histology in protocol biopsies and immunological monitoring. Transpl Int 28: 1283-1290. 14. Dunne S Shannon B Dunne C Cullen W 2013 A review of the differences and similarities between generic drugs and their originator counterparts including economic benefts associated with usage of generic medicines using Ireland as a case study. BMC Pharmacol Toxicol 14: 1. OMICS International: Open Access Publication Benefits Features Unique features: • Increased global visibility of articles through worldwide distribution and indexing • Showcasing recent research output in a timely and updated manner • Special issues on the current trends of scientifc research Special features: • 700+ Open Access Journals • 50000+ editorial team • Rapid review process • Quality and quick editorial review and publication processing • Indexing at major indexing services • Sharing Option: Social Networking Enabled • Authors Reviewers and Editors rewarded with online Scientifc Credits • Better discount for your subsequent articles Submit your manuscript at: http://www.omicsonline.org/submission Citation: Lindnér C Lindnér P 2017 A 1-year Comparison of Generic Tacrolimus Tacni ® and Prograf ® in Renal Transplant Patients: A Retrospective Matched Group Analysis. J Clin Exp Transplant 2: 113.

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