Tacrolimus, a calcineurin inhibitor, has been the cornerstone of immunosuppressive regimens in renal transplant over 2 decades. This has significantly improved the outcomes of renal transplant, including reduction of acute rejection episodes, improvement of renal function and graft survival, and reduction of some of the adverse effects associated with cy­closporine. However, use of tacrolimus is associated with a number of undesirable effects, such as nephrotoxicity, post­transplant diabetes mellitus, neurotoxicity, and cosmetic and electrolyte disturbances. To alleviate these effects, several strategies have been adopted to minimize or eliminate tacrolimus from maintenance regimens of immuno­suppression, with some success. This review focuses on advancements in the under­standing of the basic science related to tacrolimus and the clinical evidences that have examined the efficacy and safety of tacrolimus in renal transplant over the past 2 decades and highlights the future directions.

Key words : Nephrotoxicity, Outcomes, Rejection

Introduction

The central issue in renal transplant (RT) is the prevention of allograft rejection, which has led to the development of a wide range of immunosuppressive agents. Since the first successful RT performed between identical twins in the Peter Brent Brigham Hospital (Boston, MA, USA) on 23 December 1954 by Murray and associates, RT has become a routine procedure.1 According to the World Health Organization, in 2013, a total of 78 952 kidney trans­plants were performed in 104 countries worldwide.² When a kidney is transplanted from a HLA nonidentical individual, the recipient mounts an alloimmune response that leads to T-lymphocyte activation, antibody production, complement activation, allograft rejection, and transplant failure.³

In the early 1960s and 1970s, azathioprine and prednisolone were the main immunosuppressive agents used in RT, which was associated with 50% rate of acute rejection leading to reduced allograft survival. Cyclosporine, a calcineurin inhibitor (CNI), was introduced by Sir Roy Calne in Cambridge in 1982, revolutionizing RT by reducing the incidence of acute rejection to 25% and achieving significant improvements in allograft survival.⁴ Tacrolimus is a 23-member macrolide lactone (molecular mass, 803.5 Da) isolated from Streptomyces tsukubaensis, which was introduced in 1987 by Tom Starzl (Pittsburgh, PA, USA).⁵ It is a CNI similar to cyclosporine but 100 times more potent. This has further reduced the incidence of acute rejection, particularly the steroid resistant type, thus becoming an integral part of maintenance immunosuppression in RT. Since its introduction 2 decades ago, several prospective randomized trials have been conducted to evaluate its safety and efficacy, in combination with several agents, to minimize its adverse effects.^6,7

The aim of this review is to consolidate the published literature on the understanding of the basic science pertinent to clinical application of tacrolimus in RT, the evidence on its safety and efficacy, strategies adopted to minimize the adverse effects, the effect of prolonged-action formulation, and the pharmacoeconomics of generic formulations.

Literature search strategy
A systematic electronic literature search was per­formed in PubMed, EMBASE, and Cochrane Library databases from inception to April 2016 using the search terms “kidney transplantation,” “tacrolimus,” “FK506,” “Prograf,” “complications,” “toxicities,” and “outcomes.” Relevant references were compiled by using EndNote software (version X-7.4; Thomson Reuters, Philadelphia, PA, USA).

Mechanisms of action
Tacrolimus inhibits T-cell activation by binding to the FK-binding protein, which is an intracytoplasmic protein. The complex thus formed binds to calcium-dependent and calmodulin-dependent phosphatase, the calcineurins, thereby blocking dephos­phorylation of the transcription factor, the cytosolic form of the nuclear factor of activated T cells, and preventing it from translocating into the nucleus and to the DNA promotor region, thereby inhibiting interleukin 2 synthesis. Blockade of interleukin 2 gene transcription leads to failure of T-cell clonal expansion and differentiation of precursor to mature cytotoxic T cells.^8,9

Pharmacokinetics
After oral administration, tacrolimus undergoes extensive first-pass effects via p-glycoprotein and intestinal and hepatic cytochrome P450 3A (CYP3A) enzymes.¹⁰ Tacrolimus is primarily eliminated from the body in the bile by hepatic metabolism, and less than 1% of unchanged drug is excreted in the urine.¹¹ The oral bioavailability of tacrolimus is low and exhibits large intra- and interindividual variability, ranging from 4% to 89% (mean around 25% in liver and RT recipients and in patients with renal impairment).¹² Recently, a study compared the pharmacokinetic profiles of tacrolimus in RT recipients by administering the drug by both oral and sublingual routes. Tacrolimus was administered by oral route at the scheduled dose, whereas 50% of oral dose was administered by sublingual route, taking into account the liver first-pass mechanism. After sublingual administration, analyses after dose-adjusted exposure showed significant increases in area under the concentration curve and minimum concentration was observed, indicating a better bioavailability of the sublingual route compared with the oral route. This saved costs and offered an attractive option to intravenous and oral admin­istration.¹³

Concomitant use of drugs, which induce or inhibit CYP3A enzymes, alters the drug clearance and mandates more vigilant therapeutic drug monitoring and dose adjustment.¹⁴ Changes in the motility of the gut affects absorption and overall drug exposure. Paradoxically, in diarrhea, tacrolimus trough levels increase due to decreased intestinal p-glycoprotein activity of the damaged mucosa.¹⁵

Higher doses of tacrolimus are required in black patients due to pharmacogenomic differences in the p-glycoprotein and CYP3A4 and CYP3A5 enzyme expression, which is present in 70% to 80% of black individuals but in only 5% to 10% of white individuals.^16,17 Although CYP3A5 polymorphism significantly influenced the tacrolimus dose required to achieve the target concentration, the impact of CYP3A5 polymorphism on biopsy-proven acute rejection (BPAR) has not been observed.¹⁸ In a meta-analysis by Rojas and associates, the expressers of CYP3A genotype were found to be at a higher risk of acute rejection and chronic nephrotoxicity. Those patients at risk of developing tacrolimus-related complications could be identified before their RT.¹⁹ Steroids induce CYP3A and p-glycoprotein enzymes, thereby increasing the requirement of tacrolimus with higher doses of steroids. This has clinical implication in RT, when the steroid is tapered, leading to increased blood levels of tacrolimus and causing nephrotoxicity.²⁰

Adverse effects
Nephrotoxicity is the most well-known adverse effect of tacrolimus, contributing to chronic allograft injury, a major cause of graft failure in RT recipients.²¹ Tacrolimus-induced nephrotoxicity has been reported to occur in 10% to 20% of nonrenal transplant recipients culminating in RT.²² Tacrolimus causes vasoconstriction of the afferent and efferent glomerular arterioles and reductions in renal blood flow and glomerular filtration rate (GFR) and causes substantial impairment of endothelial cell function. This leads to reduced production of vasodilators (prostaglandins and nitric oxide) and enhanced release of vasoconstrictors (endothelin and throm­boxane). In addition, transforming growth factor β1, endothelin 1, and the production of reactive oxygen and nitrogen species have also been implicated.²³

In an earlier report, acute reversible nephro­toxicity was reported in 17% of RT patients.²⁴ Posttransplant diabetes mellitus (PTDM) is another major adverse effect of tacrolimus and is a significant risk factor for cardiovascular disease, which, in one study, occurred in 29.5% of RT recipients.²⁵ Risk factors for PTDM after RT include increased age, black ethnicity, hepatitis C infection, and con­comitant administration of high doses of steroids.²⁶

Neurotoxicity due to tacrolimus can range from mild symptoms such as headache and tremor to more severe effects such as seizures, delirium, and coma. Posterior reversible encephalopathy syndrome is a serious complication of tacrolimus therapy, which is due to reversible vasogenic edema of subcortical white matter and can lead to irreversible cytotoxic edema with significant morbidity and mortality. Posterior reversible encephalopathy syndrome can occur with therapeutic doses of tacrolimus and is reversible with dose reduction or cessation of therapy.^27,28

Other adverse effects include alopecia and electrolyte imbalances, such as hyperkalemia and hypomagnesemia.^29,30 The cardiovascular effects, such as hypertension and hyperlipidemia, and cosmetic effects, such as gingival hyperplasia and hirsutism, which are frequently associated with cyclosporine, are less frequent with tacrolimus, and modest clinical improvements can occur with switching to tacrolimus.³¹

BK polyoma virus infection occurs in up to 10% of RT recipients, causing premature transplant loss.³² Tacrolimus activates replication of BK polyoma virus in the renal tubular epithelial cells by binding with FK-binding proteins, inhibiting proliferation of BK virus-specific T cells.³³ A higher trough level (> 10 ng/mL) is considered as a risk factor for BK virus infection after RT.³⁴

Tacrolimus versus cyclosporine
Clinical trials of cyclosporine in RT began in Cambridge, UK, in 1978, and cyclosporine was intro­duced into immunosuppression regimen protocols worldwide in 1982.^35,36 Since the introduction of tacrolimus, several studies have been conducted to compare the safety and efficacy of the 2 drugs. In a phase III US multicenter trial comparing the efficacy and safety of tacrolimus versus cyclosporine, there was a significantly low incidence of acute rejection at 1 year in the tacrolimus group (30.7% vs 46.4%; P < .001) and low incidence of moderate-to-severe rejection (10.8% vs 26.5%). At 5 years, rate of patients with serum creatinine levels > 150 μg/L was lower in the tacrolimus group (40.4% vs 62%; P < .001), but tremor and paresthesia were more common in the tacrolimus group. There were no differences in the 1-year patient survival (95.6% vs 96.6%) and graft survival (91.2% vs 87.9%) rates between the 2 groups. The incidence of PTDM was 19.9% in the tacrolimus group and 4.0% in the cyclosporine group (P < .001) and was reversible in some patients.³⁷

A randomized prospective trial comparing tacrolimus-azathioprine, cyclosporine-mycopheno­late mofetil (MMF), and tacrolimus-MMF showed no differences in acute rejection episodes, but there was a significant difference in the number of patients requiring antithymocyte globulin (4.2% in tacrolimus-MMF arm versus 10.7% in the cyclosporine-MMF arm and 11.8% in the tacrolimus-azathioprine arm; P < .05). There were no differences in patient and graft survival at 1, 2, or 3 years.38 Combination of sirolimus or MMF with tacrolimus-based regimens did not show any difference in the incidence of acute rejection and patient or graft survival.³⁹ Comparisons of dual therapy (tacrolimus-prednisolone) with triple therapy (tacrolimus-MMF-prednisolone) showed significantly lower incidence of acute rejection in the triple therapy group (44% vs 27%; P < .01). There were no differences in patient and graft survival, incidence of delayed graft function, cytomegalovirus infection, and PTDM between the 2 groups.⁴⁰

Webster and associates, in a meta-analysis of 30 trials (4102 patients) comparing tacrolimus with cyclosporine, showed significant reductions in graft loss in tacrolimus-treated recipients (risk ratio [RR] = 0.56), less acute rejection (RR = 0.69), less steroid-resistant rejection (RR = 0.49), but more PTDM requiring insulin (RR = 1.86), tremor, headache, diarrhea, dyspepsia, and vomiting. Cyclosporine-treated recipients had significantly more constipation and cosmetic adverse effects. No differences were seen in infection or malignancy.⁴¹ Several trials have confirmed better renal function associated with tacrolimus compared with cyclo­sporine.^42,43

Tacrolimus in combination with mycophenolate mofetil and azathioprine
To reduce adverse effects and to improve its efficacy, tacrolimus has been used in combination with MMF, azathioprine, steroids, and induction agents such as antithymocyte globulin, interleukin 2 receptor antagonists, rituximab, and alemtuzumab. As the number of RTs utilizing kidney donations after death has significantly increased in the past decade, a higher incidence of delayed graft function has been observed in this group of RT recipients compared with recipients of donations after brain death or living donors.⁴⁴ In patients with delayed graft function, there was a trend toward improved graft survival in the tacrolimus-based treatment group at 1 year. The trend became more significant when the tacrolimus-MMF arm was compared with the cyclosporine-MMF arm at 2 and 3 years. At 3 years, the serum creatinine level was significantly lower in the tacrolimus-treated patients.³⁹

In a European randomized study involving 500 patients, addition of azathioprine to a tacrolimus and steroid-based regimen did not show any difference in graft survival, patient survival, and acute or chronic rejection.⁴⁵ In a single center trial evaluating the combination of MMF and tacrolimus plus steroid versus tacrolimus and steroid, a decreased risk of acute rejection episodes from 44% to 27% was observed at 1 year in the former group.46 Thus, tacrolimus when combined with MMF led to better outcomes than when used in combination with azathioprine.

Rescue therapy
Tacrolimus has been proven effective as rescue therapy in cyclosporine-treated patients with acute cellular, vascular, and steroid-resistant acute rejection episodes. In a 5-year follow-up of 169 patients who were converted from cyclosporine to tacrolimus for refractory rejection, a 74% success rate and a mean serum creatinine level of 202 μmol/L were shown. Steroid withdrawal was achieved in 22% of patients after conversion to tacrolimus.⁴⁷ A prospective, randomized, multicenter comparative trial has confirmed the efficacy of tacrolimus conversion in patients with acute rejection who were on cyclosporine-based immunosuppression. Rescue therapy with tacrolimus-based regimens reduced the incidence of recurrent acute rejection to 8.8% versus 34.1% (P < .002).48

ABO-incompatible and sensitized transplants
ABO-incompatible RT has become an established practice in RT, which is performed by utilizing perioperative antibody depletion (rituximab and plasmapheresis) and tacrolimus-based immunosup­pressive regimens. Several studies have shown successful outcomes in terms of BPAR rate, renal function, and graft and patient survival rates. Ishida and associates compared the outcomes of ABO-incompatible living-related RT between patients who had received steroids, cyclosporine, azathioprine, antilymphocyte globulin, and deoxyspergualin (group 1; n = 105) versus steroids, tacrolimus, and MMF (group 2; n = 117). The incidence of BPAR was significantly higher in group 1 than in group 2 (48% vs 15%; P < .001). There was a significant difference in the 1- and 5-year graft survival rates between groups 1 and 2 (1 year: 78% vs 94%; 5 year: 73% vs 90%; P = .008). Thus, the tacrolimus-MMF combination provided better outcomes than the cyclosporine-based regimen.^49,50

Treatment of highly sensitized RT recipients is challenging because of increased risk of graft loss from antibody-mediated rejection. Several induction immunosuppression protocols have been utilized, which may include antithymocyte globulin, alem­tuzumab, rituximab, plasmapheresis, and intravenous immunoglobulin. The maintenance regimen used in all studies consisted of tacrolimus, MMF, and steroids. The outcomes with regard to BPAR and graft and patient survivals were satisfactory.^51,52

Toxicity-limiting studies
Several prospective studies have been conducted to limit the toxicities of tacrolimus and cyclosporine either by dose reduction or elimination from the regimens. In a large European study on tacrolimus conversion for cyclosporine-induced toxicities, successful outcomes were achieved in resolving gingival hyperplasia, hypertrichosis, hyperlipidemia, and hypertension.⁵³ With the use of tacrolimus, nephrotoxicity leading to chronic allograft injury and metabolic adverse effects, particularly PTDM, have generated major concerns. Several CNI-minimizing or sparing protocols have been examined to assess the efficacy of low-dose CNIs in combination with other agents, which have been shown to reduce premature graft loss. Two large randomized trials, ORION54 and Symphony,⁵⁵ have suggested that the combination of sirolimus and MMF is inferior to low-dose tacrolimus and MMF-based triple therapy.

In the Efficacy Limiting Toxicity Elimination Symphony study, a regimen of daclizumab, MMF, and corticosteroids in combination with low-dose tacrolimus was superior to regimens involving daclizumab induction plus either low-dose cyclosporine, low-dose sirolimus, or standard-dose cyclosporine without induction in improving renal function, allograft survival, and acute rejection rates.55,56 Flechner and associates, in a prospective randomized trial (ORION study), compared the safety and efficacy of sirolimus-based regimens with tacrolimus and MMF. Renal transplant recipients were randomized into group 1 (sirolimus-tacrolimus, with week 13 tacrolimus elimination; n = 152), group 2 (sirolimus-MMF; n = 152), or group 3 (tacrolimus-MMF; n = 139). The incidence of BPAR at 1 and 2 years was 15.2% and 17.4% for group 1, 31.3% and 32.8% for group 2, and 8.2% and 12.3% for group 3 (group 2 vs 3, P < .05). Graft survival rate, patient survival rate, and mean GFR were similar in the 3 groups. In groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. The PTDM was greater in tacrolimus recipients (groups 1 and 3 vs 2, 17% vs 6%; P = .004). The sirolimus-based regi­mens were not associated with improved outcomes in RT recipients.⁵⁴

The Sirolimus Renal Conversion Trial (CONVERT trial) examined the effects of converting from CNI (tacrolimus or cyclosporine) to sirolimus as maintenance therapy and showed (particularly in the subgroup with baseline GFRs of > 40 mL/min and urinary protein-to creatinine ratios of ≤ 0.11) superior renal function in patients treated with sirolimus for 12 to 24 months.57 A randomized control trial by Guerra and associates suggested maintenance therapy with tacrolimus-MMF was more favorable than either tacrolimus-sirolimus or cyclosporine-sirolimus.⁵⁸

To address the question regarding whether nephrotoxicity is an issue with tacrolimus, Ekberg and associates pooled data from 3 large randomized de novo RT studies (Symphony, Fixed-Dose con­centration controlled, and OptiCept) and explored the relations of renal function at 1 year after RT (estimated GFR) with tacrolimus levels and MMF dose measured over the previous 6 months. Lower tacrolimus levels and higher MMF doses were associated with significantly better renal function. It was concluded that tacrolimus does have a moderate but consistent nephrotoxic effect even in efficient immunosuppressive regimens where it was used at lower doses than previous years.⁵⁹

Steroid withdrawal and steroid-free regimens
Long-term use of steroids is associated with con­siderable morbidity, including hypertension, hyper­lipidemia, PTDM, growth retardation, osteoporosis, fractures, Cushing syndrome, serious infections, and gastrointestinal events. Several studies have exam­ined the outcomes of early steroid withdrawal or steroid-free tacrolimus-based immunosuppression regimens.⁶⁰

Vincenti and associates conducted a multicenter study to investigate the feasibility to withdraw steroids early after RT with the use of daclizumab, tacrolimus, and MMF. Patients received either 2 doses of daclizumab (1 mg/kg) and 100 mg of prednisolone for the first 3 days (daclizumab group; n = 186) or steroids tapered to 0 mg at week 16 (control group; n = 178). All patients received tacrolimus and MMF. The incidence of BPAR (15% vs 14%) and graft survival at 1 year (91% vs 90%) were similar between the 2 groups. Mean arterial blood pressure, hyperlipidemia, and PTDM were lower in the daclizumab group than in the control group. It was concluded that, with daclizumab induction, it was possible to withdraw steroids at 3 days after RT.61 A meta-analysis of 9 randomized control trials (1820 participants) assessed the effects of steroid withdrawal between 3 and 6 months after RT in patients on CNI plus MMF. Use of cyclosporine was associated with an increased incidence of BPAR (RR = 1.61). In contrast, tacrolimus allowed steroid withdrawal without increased incidence of BPAR.⁶²

Kramer and associates, in the antibody, tacrolimus, and steroid withdrawal (ATLAS) study, evaluated the long-term efficacy and safety of 2 steroid-free immunosuppressive regimens after RT: (1) basi­liximab induction therapy followed by tacrolimus monotherapy and tacrolimus plus MMF and (2) a standard tacrolimus-based triple regimen (tacrolimus-MMF-steroids). Most acute rejection episodes occurred during the main 6-month study, when the incidence was higher, in the corticosteroid-free groups (26.1% in the tacrolimus-basiliximab group and 30.5% in the tacrolimus-MMF group vs 8.2% in the triple therapy group; P < .001). In the time interval from 6 months to 3 years after RT, the incidence of BPAR was low and similar (2.1%, 2.2%, and 2.2%). Graft survival (92.7%, 92.5%, and 92.5%), patient survival (93.1%, 96.4%, and 97%), and renal function were similar between the groups. There was a trend toward improved cardiovascular risk in the tacrolimus-basiliximab group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use.⁶³

Prolonged-release tacrolimus
Nonadherence is a common and major cause of RT failure and amounts to 7-fold risk of graft failure in nonadherent compared with adherent individuals (odds ratio = 7.1; P < .001).64 To address the nonad­herence issue, a once-a-day formulation of tacrolimus (Advagraf, Astellas Pharma Limited, UK; and Envarsus, Chiesi Limited, UK) has been approved in several countries since 2007. Several prospective studies have assessed the efficacy, safety, acute rejection, graft dysfunction, and graft loss of a daily preparation with twice daily formulation (Prograf, Astellas Pharma Limited, UK; and Adoport, Sandoz Limited, UK), both in de novo initiation or conversion settings. A review that included all published phase III/IV studies in de novo initiation concluded that daily is as effective as twice daily regimens in preventing acute rejection, graft dysfunction, and graft loss.⁶⁵

The early conversion from twice daily to daily tacrolimus has the theoretical advantages of reducing the odds of underexposure with tacrolimus in the early posttransplant setting; however, data are scarce regarding efficacy and safety of the early conversion. In the OSAKA trial, which included patients representative of the European kidney transplant population, a daily tacrolimus immunosuppression regimen (0.2 mg/kg/d) without induction showed similar efficacy to a twice daily tacrolimus regimen (0.2 mg/kg/d).66 In an observational study involving 310 stable renal transplant recipients, the incidence of nonadherence was 23.5%. A shift from twice daily to daily tacrolimus was performed in 121 patients, with the remainder as the control group. At 6 months, a questionnaire survey showed significant reduction in pill number and improved adherence (+36%; P < .05 vs basal), with no change in controls. Decreased tacrolimus trough levels after 3 and 6 months (-9%) despite a slight increase in drug dosage (+6.5%) were observed in the shift group, with no clinical adverse effects.⁶⁷

Recently, a French expert panel recommended performing early conversion (1:1 mg) after bowel movement had resumed and a stable state of the tacrolimus trough level had been achieved. If the trough level with a twice daily formulation is below the target range, conversion should be postponed.68 After de novo initiation, tacrolimus systemic exposure is reduced by approximately 30% with the daily formulation. The reduction is lower if the first dose is given preoperatively. Therefore, it is recom­mended to initiate tacrolimus daily preoperatively. After conversion, a 10% to 15% decrease in trough level is observed, which does not translate into an equivalent decrease in area under the curve. There is no difference in the glycemic control, renal function, and patient and graft survival rates between the 2 groups, but there is trend for improved adherence with daily formulation.⁶⁹

Costimulation blockade
There are no data available that have compared the efficacy and safety of tacrolimus versus belatacept-based immunosuppression regimens in RT. Belatacept, a fusion protein composed of the Fc fragment of human immunoglobulin G1, links to the extracellular domain of CTLA-4, selectively inhibiting T-cell activation through costimulation blockade.70 Belatacept has been in use since 2006 in two phase III studies: the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) and the BENEFIT-Extended Criteria Donors (BENEFIT-EXT) trial.^71-73 These have as­sessed more intensive and less intensive regimens of belatacept versus cyclosporine in adults receiving kidney transplants from living or standard criteria deceased donors. The belatacept group had higher incidence of acute rejection and posttransplant lymphoproliferative disorder (PTLD). The major limitation of the trial was the use of cyclosporine, a less contemporary immunosup­pressive agent. Although one can speculate similar outcomes with the use of tacrolimus, a head-to-head trial is warranted to draw definitive conclusions.
In the Cochrane review performed in 2014, which included 5 studies and compared belatacept with CNI (3 cyclosporine; n = 478 recipients) and 2 tacrolimus (n = 43 recipients), no differences in the effectiveness of belatacept and CNI in preventing acute rejection, graft loss, and death were shown. However, treatment with belatacept was associated with less chronic kidney scarring and better kidney transplant function. Treatment with belatacept was also associated with better blood pressure and lipid profile and a lower incidence of diabetes versus treatment with a CNI. Important adverse effects (particularly PTLD) remain poorly reported. The long-term benefit was still to be reported.⁷⁴

In a recent report of registry data by Wen and associates, which compared clinical outcomes between belatacept- and tacrolimus-treated adult RT recipients, 458 patients of 50 244, who had received belatacept alone, experienced a higher risk for 1-year acute rejection, with highest rates associated with nonlymphocyte-depleting induction (RR = 2.65; P < .0001). There were no significant differences in rejection rates between belatacept-tacrolimus and tacrolimus alone. The incidence of PTDM was significantly lower with belatacept-tacrolimus and belatacept alone versus tacrolimus alone (1.7% vs 2.2% vs 3.8%; P =.01). Despite improved graft function and metabolic complications with belatacept alone, it was advised to add short-term tacrolimus in the first year posttransplant and consider lymphocyte induction in patients with high rejection risk.⁷⁵

Generic tacrolimus
There has been an increasing trend in substitution of brand formulations with generic formulations in RT for cost-containment measures. Momper and asso­ciates evaluated the bioequivalence, safety, and efficacy of substitution of reference product (Prograf, Astellas Pharma, Tokyo, Japan) with generic tacrolimus formulation (produced by Sandoz, Holzkirchen, Germany) in RT recipients with stable renal function. The mean tacrolimus concentration-to-dose ratio (± standard deviation) was 184.1 ± 123.2 ng/mL/(mg/kg/day) for the reference product and 154.7 ± 87.8 ng/mL/(mg/kg/day) for the generic product (P < .05). Actual trough concentrations declined by an average of 0.87 ng/mL in kidney transplant patients after the switch, when accounting for all significant covariates. No changes were observed in renal function, and no cases of acute rejection occurred after the substitution. It was concluded that reference tacrolimus can be safely substituted with the generic product, provided trough concentrations are closely monitored after the substitution.⁷⁶

A systematic review and meta-analysis evaluated the clinical efficacy and bioequivalence of generic tacrolimus and Prograf (12 studies) in solid-organ transplant with reference to the outcomes, including patient survival, allograft survival, acute rejection, adverse events, and bioequivalence. Pooled analysis of randomized control trials in patients with RT that reported bioequivalence criteria showed that Prograf (3 studies) was not bioequivalent to generic preparations. Acute rejection was rare but did not differ between groups. High-quality data showing bioequivalence and clinical efficacy of generic immunosuppressive drugs in patients with transplants were lacking; hence, well-designed studies were recommended.⁷⁷

Future directions
Evidence from the studies conducted to assess the safety and efficacy of tacrolimus in RT unequivocally confirm the positive benefits achieved in RT recipients. Tacrolimus has proven to be a cornerstone immunosuppression and the dominant CNI in RT for the past 2 decades and is likely to continue to retain its place until new drugs, free from the adverse effects inherent to tacrolimus, become available. Hyperlipidemia, hypertension, and risk of rejection argue for tacrolimus, whereas a high risk of diabetes (old age or obesity) argues for cyclosporine. In clinical practice, it is important to exploit the strength of individual immunosuppressive agents and adopt a regimen tailored to individual patients based on their immunologic risk profiles. Research endeavors in RT directed to achieve this goal is the way forward.

References:

1. Merrill JP, Murray JE, Harrison JH, Guild WR. Landmark article Jan 28, 1956: Successful homotransplantation of the human kidney between identical twins. By John P. Merrill, Joseph E. Murray, J. Hartwell Harrison, and Warren R. Guild. JAMA. 1984;251(19):2566-2571.
   CrossRef - PubMed
2. World Health Organization Web. Kidney Transplant Activity in 2013 in 104 Countries. http://wwwtransplant-observatoryorg/Pages/Factsaspx; Accessed 2016 May 19.
3. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004;351(26):2715-2729.
   CrossRef - PubMed
4. Calne RY. The initial study of the immunosuppressive effects of 6-mercaptopurine and azathioprine in organ transplantation and a few words on cyclosporin A. World J Surg. 1982;6(5):637-640.
   CrossRef - PubMed
5. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet. 1989;2(8670):1000-1004.
   CrossRef - PubMed
6. Augusto JF, Subra JF, Onno C, et al. Long-term maintenance immunosuppressive regimen with tacrolimus monotherapy. Ann Transplant. 2013;18:368-377.
   CrossRef - PubMed
7. Berloco P, Rossi M, Pretagostini R, Sociu-Foca Cortesini N, Cortesini R. Tacrolimus as cornerstone immunosuppressant in kidney transplantation. Transplant Proc. 2001;33(1-2):994-996.
   CrossRef - PubMed
8. Solez K, Vincenti F, Filo RS. Histopathologic findings from 2-year protocol biopsies from a U.S. multicenter kidney transplant trial comparing tarolimus versus cyclosporine: a report of the FK506 Kidney Transplant Study Group. Transplantation. 1998;66(12):1736-1740.
   CrossRef - PubMed
9. Rowshani AT, Scholten EM, Bemelman F, et al. No difference in degree of interstitial Sirius red-stained area in serial biopsies from area under concentration-over-time curves-guided cyclosporine versus tacrolimus-treated renal transplant recipients at one year. J Am Soc Nephrol. 2006;17(1):305-312.
   CrossRef - PubMed
10. Vanhove T, Annaert P, Kuypers DR. Clinical determinants of calcineurin inhibitor disposition: a mechanistic review. Drug Metab Rev. 2016;48(1):88-112.
    CrossRef - PubMed
11. Scott LJ, McKeage K, Keam SJ, Plosker GL. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs. 2003;63(12):1247-1297.
    CrossRef - PubMed
12. Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995;29(6):404-430.
    CrossRef - PubMed
13. Federico S, Carrano R, Sabbatini M, et al. Sublingual administration improves systemic exposure of tacrolimus in kidney transplant recipients: comparison with oral administration. Eur J Clin Invest. 2016;46(7):651-657.
    CrossRef - PubMed
14. Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet. 2000;38(2):111-180.
    CrossRef - PubMed
15. Lemahieu W, Maes B, Verbeke K, Rutgeerts P, Geboes K, Vanrenterghem Y. Cytochrome P450 3A4 and P-glycoprotein activity and assimilation of tacrolimus in transplant patients with persistent diarrhea. Am J Transplant. 2005;5(6):1383-1391.
    CrossRef - PubMed
16. Macphee IA, Fredericks S, Mohamed M, et al. Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and South Asians. Transplantation. 2005;79(4):499-502.
    CrossRef - PubMed
17. Turolo S, Tirelli AS, Ferraresso M, et al. Frequencies and roles of CYP3A5, CYP3A4 and ABCB1 single nucleotide polymorphisms in Italian teenagers after kidney transplantation. Pharmacol Rep. 2010;62(6):1159-1169.
    CrossRef - PubMed
18. Yaowakulpatana K, Vadcharavivad S, Ingsathit A, et al. Impact of CYP3A5 polymorphism on trough concentrations and outcomes of tacrolimus minimization during the early period after kidney transplantation. Eur J Clin Pharmacol. 2016;72(3):277-283.
    CrossRef - PubMed
19. Rojas L, Neumann I, Herrero MJ, et al. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. Pharmacogenomics J. 2015;15(1):38-48.
    CrossRef - PubMed
20. Anglicheau D, Legendre C, Thervet E. Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: from retrospective analyses to prospective studies. Transplant Proc. 2007;39(7):2142-2144.
    CrossRef - PubMed
21. Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349(24):2326-2333.
    CrossRef - PubMed
22. Stratta P, Canavese C, Quaglia M, et al. Posttransplantation chronic renal damage in nonrenal transplant recipients. Kidney Int. 2005;68(4):1453-1463.
    CrossRef - PubMed
23. Lamas S. Cellular mechanisms of vascular injury mediated by calcineurin inhibitors. Kidney Int. 2005;68(2):898-907.
    CrossRef - PubMed
24. Katari SR, Magnone M, Shapiro R, et al. Clinical features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant recipients. Clin Transplant. 1997;11(3):237-242.
    PubMed
25. Weng LC, Chiang YJ, Lin MH, et al. Association between use of FK506 and prevalence of post-transplantation diabetes mellitus in kidney transplant patients. Transplant Proc. 2014;46(2):529-531.
    CrossRef - PubMed
26. Demirci MS, Toz H, Yilmaz F, et al. Risk factors and consequences of post-transplant diabetes mellitus. Clin Transplant. 2010;24(5):E170-177.
    CrossRef - PubMed
27. Toledo Perdomo K, Navarro Cabello MD, Perez Saez MJ, Ramos Perez MJ, Aguera Morales ML, Aljama Garcia P. Reversible acute encephalopathy with mutism, induced by calcineurin inhibitors after renal transplantation. J Nephrol. 2012;25(5):839-842.
    CrossRef - PubMed
28. Arnold R, Pussell BA, Pianta TJ, Lin CS, Kiernan MC, Krishnan AV. Association between calcineurin inhibitor treatment and peripheral nerve dysfunction in renal transplant recipients. Am J Transplant. 2013;13(9):2426-2432.
    CrossRef - PubMed
29. Higgins R, Ramaiyan K, Dasgupta T, et al. Hyponatraemia and hyperkalaemia are more frequent in renal transplant recipients treated with tacrolimus than with cyclosporin. Further evidence for differences between cyclosporin and tacrolimus nephrotoxicities. Nephrol Dial Transplant. 2004;19(2):444-450.
    CrossRef - PubMed
30. Ushigome H, Yoshimura N, Okamoto M, et al. Two cases of tacrolimus-induced alopecia following kidney transplantation. Transplant Proc. 1999;31(7):2885-2886.
    CrossRef -
    PubMed
31. Krejci K, Tichy T, Bachleda P, Zadrazil J. Calcineurin inhibitor-induced renal allograft nephrotoxicity. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010;154(4):297-306.
    CrossRef - PubMed
32. Jamboti JS. BK virus nephropathy in renal transplant recipients. Nephrology (Carlton). 2016;21(8):647-654.
    CrossRef - PubMed https://www.ncbi.nlm.nih.gov/pubmed/26780694
33. Hirsch HH, Yakhontova K, Lu M, Manzetti J. BK Polyomavirus replication in renal tubular epithelial cells is inhibited by sirolimus, but activated by tacrolimus through a pathway involving FKBP-12. Am J Transplant. 2016;16(3):821-832.
    CrossRef - PubMed
34. Borni-Duval C, Caillard S, Olagne J, et al. Risk factors for BK virus infection in the era of therapeutic drug monitoring. Transplantation. 2013;95(12):1498-1505.
    CrossRef - PubMed
35. Calne RY, Rolles K, White DJ, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet. 1979;2(8151):1033-1036.
    CrossRef - PubMed
36. Calne RY, White DJ, Thiru S, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet. 1978;2(8104-5):1323-1327.
    CrossRef - PubMed
37. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation. 1997;63(7):977-983.
    CrossRef - PubMed
38. Johnson C, Ahsan N, Gonwa T, et al. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation. 2000;69(5):834-841.
    CrossRef - PubMed
39. Gonwa T, Mendez R, Yang HC, et al. Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months. Transplantation. 2003;75(8):1213-1220.
    CrossRef - PubMed
40. Shapiro R, Jordan ML, Scantlebury VP, et al. A prospective, randomized trial of tacrolimus/prednisone versus tacrolimus/prednisone/mycophenolate mofetil in renal transplant recipients. Transplantation. 1999;67(3):411-415.
    CrossRef - PubMed
41. Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ. 2005;331(7520):810.
    CrossRef - PubMed
42. Jurewicz WA. Tacrolimus versus cyclosporin immunosuppression: long-term outcome in renal transplantation. Nephrol Dial Transplant. 2003;18 Suppl 1:i7-11.
    CrossRef - PubMed
43. Vincenti F, Friman S, Scheuermann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant. 2007;7(6):1506-1514.
    CrossRef - PubMed
44. Chapman J, Bock A, Dussol B, et al. Follow-up after renal transplantation with organs from donors after cardiac death. Transpl Int. 2006;19(9):715-719.
    CrossRef - PubMed
45. Pascual J, Segoloni G, Gonzalez Molina M, et al. Comparison between a two-drug regimen with tacrolimus and steroids and a triple one with azathioprine in kidney transplantation: results of a European trial with 3-year follow up. Transplant Proc. 2003;35(5):1701-1703.
    CrossRef - PubMed
46. Ciancio G, Burke GW, Gaynor JJ, et al. A randomized long-term trial of tacrolimus and sirolimus versus tacrolimus and mycophenolate mofetil versus cyclosporine (NEORAL) and sirolimus in renal transplantation. I. Drug interactions and rejection at one year. Transplantation. 2004;77(2):244-251.
    CrossRef - PubMed
47. Jordan ML, Naraghi R, Shapiro R, et al. Tacrolimus rescue therapy for renal allograft rejection--five-year experience. Transplantation. 1997;63(2):223-228.
    CrossRef - PubMed
48. Dudley CR, European Tacrolimus Renal Rejection Study G. Conversion at first rejection: a prospective trial comparing cyclosporine microemulsion with tacrolimus in renal transplant recipients. Transplant Proc. 2001;33(1-2):1034-1035.
    CrossRef - PubMed
49. Flint SM, Walker RG, Hogan C, et al. Successful ABO-incompatible kidney transplantation with antibody removal and standard immunosuppression. Am J Transplant. 2011;11(5):1016-1024.
    CrossRef - PubMed
50. Ishida H, Miyamoto N, Shirakawa H, et al. Evaluation of immunosuppressive regimens in ABO-incompatible living kidney transplantation--single center analysis. Am J Transplant. 2007;7(4):825-831.
    CrossRef - PubMed
51. Mattiazzi AD, Centeno A, Amador A, et al. Highly sensitized patients: Miami Transplant Institute Experience. Clin Transpl. 2014:171-178.
    PubMed
52. Montgomery RA, Lonze BE, King KE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med. 2011;365(4):318-326.
    CrossRef - PubMed
53. Margreiter R, Pohanka E, Sparacino V, et al. Open prospective multicenter study of conversion to tacrolimus therapy in renal transplant patients experiencing ciclosporin-related side-effects. Transpl Int. 2005;18(7):816-823.
    CrossRef - PubMed
54. Flechner SM, Glyda M, Cockfield S, et al. The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. Am J Transplant. 2011;11(8):1633-1644.
    CrossRef - PubMed
55. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562-2575.
    CrossRef - PubMed
56. Ekberg H, Bernasconi C, Tedesco-Silva H, et al. Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation. Am J Transplant. 2009;9(8):1876-1885.
    CrossRef - PubMed
57. Schena FP, Pascoe MD, Alberu J, et al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation. 2009;87(2):233-242.
    CrossRef - PubMed
58. Guerra G, Ciancio G, Gaynor JJ, et al. Randomized trial of immunosuppressive regimens in renal transplantation. J Am Soc Nephrol. 2011;22(9):1758-1768.
    CrossRef - PubMed
59. Ekberg H, van Gelder T, Kaplan B, Bernasconi C. Relationship of tacrolimus exposure and mycophenolate mofetil dose with renal function after renal transplantation. Transplantation. 2011;92(1):82-87.
    CrossRef - PubMed
60. Gheith OA, Nematalla AH, Bakr MA, Refaie A, Shokeir AA, Ghoneim MA. Steroid avoidance reduce the cost of morbidities after live-donor renal allotransplants: a prospective, randomized, controlled study. Exp Clin Transplant. 2011;9(2):121-127.
    PubMed
61. ter Meulen CG, van Riemsdijk I, Hene RJ, et al. Steroid-withdrawal at 3 days after renal transplantation with anti-IL-2 receptor alpha therapy: a prospective, randomized, multicenter study. Am J Transplant. 2004;4(5):803-810.
    CrossRef - PubMed
62. Pascual J, Galeano C, Royuela A, Zamora J. A systematic review on steroid withdrawal between 3 and 6 months after kidney transplantation. Transplantation. 2010;90(4):343-349.
    CrossRef - PubMed
63. Kramer BK, Klinger M, Vitko S, et al. Tacrolimus-based, steroid-free regimens in renal transplantation: 3-year follow-up of the ATLAS trial. Transplantation. 2012;94(5):492-498.
    CrossRef - PubMed
64. Butler 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(5):769-776.
    CrossRef - PubMed
65. McCormack PL. Extended-release tacrolimus: a review of its use in de novo kidney transplantation. Drugs. 2014;74(17):2053-2064.
    CrossRef - PubMed
66. Albano L, Banas B, Klempnauer JL, et al. OSAKA trial: a randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation. Transplantation. 2013;96(10):897-903.
    CrossRef - PubMed
67. Sabbatini M, Garofalo G, Borrelli S, et al. Efficacy of a reduced pill burden on therapeutic adherence to calcineurin inhibitors in renal transplant recipients: an observational study. Patient Prefer Adherence. 2014;8:73-81.
    CrossRef - PubMed
68. Caillard S, Moulin B, Buron F, et al. Advagraf((R)) , a once-daily prolonged release tacrolimus formulation, in kidney transplantation: literature review and guidelines from a panel of experts. Transpl Int. 2016;29(8):860-869.
    CrossRef - PubMed
69. Guirado L, Cantarell C, Franco A, et al. Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients. Am J Transplant. 2011;11(9):1965-1971.
    CrossRef - PubMed
70. Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant. 2005;5(3):443-453.
    CrossRef - PubMed
71. Vincenti F, Larsen CP, Alberu J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant. 2012;12(1):210-217.
    CrossRef - PubMed
72. Charpentier B, Medina Pestana JO, Del CRM, et al. Long-term exposure to belatacept in recipients of extended criteria donor kidneys. Am J Transplant. 2013;13(11):2884-2891.
    CrossRef - PubMed
73. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. N Engl J Med. 2016;374(4):333-343.
    CrossRef - PubMed
74. Masson P, Henderson L, Chapman JR, Craig JC, Webster AC. Belatacept for kidney transplant recipients. Cochrane Database Syst Rev. 2014(11):CD010699.
    CrossRef - PubMed
75. Wen X, Casey MJ, Santos AH, Hartzema A, Womer KL. Comparison of utilization and clinical outcomes for belatacept- and tacrolimus-based immunosuppression in renal transplant recipients. Am J Transplant. 2016;16(11):3202-3211.
    CrossRef - PubMed
76. Momper JD, Ridenour TA, Schonder KS, Shapiro R, Humar A, Venkataramanan R. The impact of conversion from prograf to generic tacrolimus in liver and kidney transplant recipients with stable graft function. Am J Transplant. 2011;11(9):1861-1867.
    CrossRef - PubMed
77. Molnar AO, Fergusson D, Tsampalieros AK, et al. Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis. BMJ. 2015;350:h3163.
    CrossRef - PubMed