Thirty Years of Tacrolimus in Clinical Practice : Transplantation

Journal Logo

Reviews

Thirty Years of Tacrolimus in Clinical Practice

Ong, Song C. MD1; Gaston, Robert S. MD, FAST1,2

Author Information
Transplantation 105(3):p 484-495, March 2021. | DOI: 10.1097/TP.0000000000003350
  • Free

Abstract

INTRODUCTION

Since its discovery in 1984, and the first report of its clinical utility in 1989, tacrolimus has become a mainstay of immunosuppressant regimens, a key component of successful transplantation in thousands of patients. This prominence reflects not only the pioneering work of Thomas Starzl et al1 at the University of Pittsburgh but also efforts of numerous other investigators and clinicians that have contributed to its evolving use in transplantation over the past 30 years (Figure 1).

F1
FIGURE 1.:
Timeline of the development of tacrolimus. FDA, Food and Drug Administration; MMF, mycophenolate mofetil.

BACKGROUND

After decades of pioneering immunologic and clinical efforts by many across the globe, Joseph Murray, John Merrill, and team at the Peter Bent Brigham Hospital performed the first successful human kidney transplant in 1954 between identical twins, for whom risk of graft rejection was thought nonexistent.2 Extending these results to genetically nonidentical pairs proved more challenging and was ultimately made possible by pharmacologic immunosuppression. Initial successes occurred with 6-mercaptopurine in the late 1950s, followed by its oral analog, azathioprine (AZA), along with corticosteroids and antilymphocyte globulins.3-8 Though these novel therapies made transplantation clinically feasible, it was the introduction of cyclosporine 2 decades later that made solid organ transplantation widely successful.9

Cyclosporine, a calcineurin-phosphatase inhibitor (calcineurin inhibitor, CNI) approved by the US Food and Drug Administration (FDA) in 1983, redefined the field, substantially improving outcomes in kidney and other solid organ transplantation despite significant toxicities, most notably affecting the kidney, that limited dosing.10 AZA, deemed by some an “obsolete” immunosuppressant, corticosteroids, and antilymphocyte agents remained important, no longer as primary therapy, but as adjuncts to facilitate lower, presumably less toxic, dosing of cyclosporine.11-18 United Network of Organ Sharing data revealed that between 1988 and 1996, with the majority of patients receiving cyclosporine based immunosuppression, the 1-year survival of kidney allografts from living donors increased from 88.8% to 93.9% and that of deceased-donor kidneys increased from 75.7% to 87.7%.19 Before 1980, less than a third of liver grafts survived a year; by 1985, with cyclosporine, liver transplant survival had improved to 71% at 1 year.20,21 Similarly, 1-year survival for heart transplants improved from 55% to 82% between the eras 1975–1981 and 1982–1987.22 This was the transplant “milieu” that spawned the novel CNI, tacrolimus. After regulatory approval in the mid-1990s, it became standard of care in almost all solid organ transplant recipients in the United States and Europe within a decade.

DISCOVERY

Tacrolimus, then known as FK506, was isolated from the fermentation broth of Streptomyces tsukubaensis, a soil fungus found at the foot of Mount Tsukuba in Japan in 1984. A macrolide antibiotic, FK506 was found to have immunosuppressive effects in vitro by Kino et al23 and in animal models of transplantation by Ochiai et al.24-29

MECHANISM OF ACTION/PHARMACODYNAMICS

Tacrolimus exerts its immunosuppressive effect in the cytosol of mononuclear cells via binding to FK-binding protein-12, forming a complex that also includes calcium, calmodulin, and calcineurin. This intracellular structure blocks the phosphatase activity of calcineurin, preventing the dephosphorylation, and translocation of nuclear factor of activated T cells. Via this mechanism, tacrolimus limits transcription of genes necessary for production of proinflammatory cytokines (notably interleukin-2), thereby inhibiting signal 1 in T-lymphocyte activation.30 Though tacrolimus binds to a different receptor (FK-binding protein-12) than cyclosporine (cyclophilin), both agents inhibit the same calcineurin-dependent pathway.

PHARMACOKINETICS/THERAPEUTIC DRUG MONITORING

The pharmacokinetic profile of tacrolimus in the blood is well described.31 Its rate of absorption is variable with peak (Cmax) blood or plasma concentrations being reached in 0.5–4 hours; approximately 25% of the oral dose is bioavailable. Tacrolimus is extensively bound to red blood cells, with a mean blood to plasma ratio of about 15. Tacrolimus is completely metabolized before elimination, with minimal excretion as unchanged drug; dose adjustment is not required in renal impairment or dialysis. The mean drug half-life is 12 hours with a large interindividual variation, explained in large part by polymorphisms in cytochrome P450 enzymes CYP 3A4, CYP 3A5, and the multidrug efflux pump P-glycoprotein encoded by multidrug-resistance 1 in the intestinal mucosa.32-34 The elimination of tacrolimus is decreased in the presence of liver impairment and in the presence of drugs that inhibit CYP P450.35 Tacrolimus absorption is decreased following food, as much as 30% if taken after a moderately fatty meal; variability of absorption is least on an empty stomach.36 Diarrhea inhibits gut mucosal P-glycoprotein activity and increases bioavailability of tacrolimus.37

Assays to measure tacrolimus levels in biologic fluids were established by Tamura and colleagues in 1987.38 By 1990, the Pittsburgh group was able to establish an on-site plasma assay, greatly facilitating the delineation of pharmacokinetics to define appropriate and safe use of tacrolimus.39 Adequacy of tacrolimus exposure is typically defined as a target trough (Cmin) level in whole blood; unlike cyclosporine, trough tacrolimus levels correlate well with AUC0-12 (area under the blood concentration time curve).40,41

Target tacrolimus trough levels vary with the organ transplanted and with center-specific practice, while attempting to incorporate an individual patient’s immunologic risk profile. In general, higher target trough levels are favored early in the transplant course, with progressive reduction in target levels once graft stability is achieved, typically after the first year posttransplant. As many factors influence tacrolimus levels (eg, drug-drug and drug-food interactions, genetic factors, assay variability, and variations in generic formulations), monitoring of tacrolimus trough levels at defined intervals remains an essential component of long-term care. A high within-patient variability in tacrolimus trough levels has been associated with poorer outcomes, including increased risk of rejection and graft failure.42-44 Though difficult to assess, patient adherence may be a major factor driving within-patient variability and is potentially amenable to appropriate intervention.45,46

EARLY CLINICAL EXPERIENCE

The early clinical development of tacrolimus was driven by Dr Thomas Starzl and colleagues at the University of Pittsburgh. As animal studies had raised concerns regarding clinical toxicity, with vomiting and emaciation common in dogs, testing in healthy volunteers was not done before clinical usage.1 In 1989, Starzl et al1 reported their experience with tacrolimus in 14 liver transplant recipients. In this remarkable series, tacrolimus was used as salvage therapy in 10 patients with rejection of liver allografts despite standard of care treatment with cyclosporine and corticosteroids and 4 patients with de novo grafts. Among these patients, 2 had also received kidney transplants and a third liver, kidney, and pancreas grafts. Tacrolimus was dosed by weight at 0.15 mg/kg as a bolus intravenous infusion and continued at a weight-based dose of 0.075 mg/kg every 12 hours, until oral administration was possible. Oral therapy was dosed at 0.15 mg/kg every 12 or 24 hours. Plasma drug level monitoring demonstrated 12-hour troughs of 0.5–5 ng/mL with the intravenous infusion, and trough levels of <3 ng/mL with oral dosing. The group successfully reversed organ rejection with tacrolimus in 7 of 10 attempts. Ultimately, 2 (of these original 10 patients) who lost their grafts, along with the 4 de novo patients, underwent successful transplants using tacrolimus and low-dose steroids without rejection.

With these encouraging outcomes, the Pittsburgh group began using tacrolimus as first-line therapy in many more liver recipients (primary and retransplants), as well as in a small number of heart, lung, and heart-lung transplants, publishing these results in 1990.47 This team subsequently reported early experience with FK506 in 36 kidney transplant recipients, many of whom were high risk (highly sensitized, retransplants, and multiorgan transplants), and found graft and patient survival, as well as tolerability, to be encouraging.39 From 1989 to 1993, the Pittsburgh experience grew to 1391 liver transplants performed with tacrolimus from the outset. When compared with 1212 historical controls treated with cyclosporine, the FK506 patients had much better outcomes, with 1-year graft survival of 86.2% versus 65.5%, and graft loss from refractory rejection of only 1%–2%.48 This increment in graft survival with tacrolimus (versus cyclosporine) was similar to that noted in hepatic transplantation after the introduction of cyclosporine (versus AZA). Nephrotoxicity, neurotoxicity, and diabetogenicity were comparable to cyclosporine, with hypertension and hyperlipidemia less common with tacrolimus.39,47 Notably, the tacrolimus-treated patients did not demonstrate the cosmetic changes associated with cyclosporine use (hirsutism, gingival hyperplasia, and coarse facial changes).39,47

Subsequently, Starzl et al proceeded to conduct a prospective, single-center, randomized, and controlled trial to compare tacrolimus with cyclosporine in liver transplantation.49 From February 16, 1990, to December 26, 1991, 154 patients were recruited and randomized in near equal numbers to either cyclosporine or tacrolimus and followed until the trial’s termination in 1995. In this trial, both arms used steroids for induction, with drug crossover permitted for lack of efficacy or adverse events. Patients randomized to the tacrolimus arm were less likely to experience acute rejection at 1 year (36.2% versus 16.8%). Notably, those experiencing problems with cyclosporine (primarily rejection) were able to convert to tacrolimus (almost 60% ultimately did), with survival curves of both groups largely similar after the first year.

RANDOMIZED TRIALS AND REGULATORY APPROVAL

In order to understand the controversy surrounding ultimate regulatory approval of tacrolimus, it is important to reiterate the stature of Dr Starzl and the University of Pittsburgh in liver transplantation at the time.50 After a consensus development conference in 1983 redefined liver transplants as clinical services rather than experimental procedures, new programs sprang up rapidly in the United States.51 In the late 1980s, an excess of 500 liver transplants were performed annually in Pittsburgh, at 1 point representing up to one-third of all such procedures performed in the country.52 Surgeons from around the world flocked to Pittsburgh to undergo training in the procedure, spreading local practices globally, and leading to skyrocketing demand for access to tacrolimus. Despite the Pittsburgh experience, regulatory agencies (and even the local institutional review board at Presbyterian University Hospital in Pittsburgh) demanded randomized, controlled trials of tacrolimus before granting broad access to the drug. In a commentary titled “Randomized Trialomania,” Starzl et al53 criticized the resulting trials (from which the University of Pittsburgh was excused from participation) as not only methodologically flawed, but perhaps unethical due to lack of equipoise between treatment arms. Nonetheless, these studies went forward as designed, ultimately proving essential to global regulatory approval of tacrolimus for use in solid organ transplantation.

In 1990, 2 large multicenter liver transplant trials were initiated in the United States and Europe, comparing cyclosporine (Sandimmune) to FK506, with results published in 1994.54,55 In the European trial (n = 545), a 5% increment in patient and graft survival was seen with tacrolimus (P = NS). However, as in Pittsburgh, there had been significant crossover from the cyclosporine arm to tacrolimus, with 10% of grafts surviving in the cyclosporine arm attributed to tacrolimus rescue. Results of the American trial (n = 529) were similar with 9.5% of surviving grafts in the cyclosporine arm treated with tacrolimus rescue therapy following refractory acute rejection. Ultimately, data from these 2 large multicenter trials were the basis of FDA approval for the use of tacrolimus in liver transplantation (June, 1994). By that time, tacrolimus had already been approved for use in liver transplantation in Japan (March, 1993) and for heart, liver, and kidney transplant in Germany (June, 1993).

Because of uncertainty regarding appropriate dosing (and proper combinations of immunosuppressants) in renal transplantation, approval of tacrolimus in kidney grafts lagged by several years. A phase 2, multicenter trial of 3 dosing regimens established optimal target blood levels at 5–15 ng/mL, with efficacy similar to cyclosporine among 92 patients.56 Subsequently, as in liver, 2 large multicenter, randomized trials compared tacrolimus to cyclosporine (Sandimmune) in the United States and in Europe. Results, published in 1997, mirrored the findings in the liver trials. The American trial (n = 412 recipients of deceased-donor kidneys) compared FK506 with cyclosporine (Sandimmune), in combination with AZA, corticosteroids, and depletional induction.57 One-year patient and graft survival rates were similar in both groups but with a significant reduction in biopsy-confirmed acute rejection (BCAR) with tacrolimus (30.7%) versus cyclosporine (46.4%; P = 0.001). The trial also revealed increased diabetogenicity of tacrolimus with new-onset diabetes after transplantation (NODAT) occurring in 19.9% of the tacrolimus group versus 4.0% of the cyclosporine group (P < 0.001). Allograft and patient survival did not differ at 1, 3, or 5 years, a result again often attributed to confounding caused by significant crossover to tacrolimus due to refractory rejection.58,59 If crossover from cyclosporine due to rejection was deemed graft failure, treatment failure occurred significantly less often in the tacrolimus arm.

In a contemporaneous trial in Europe, 448 kidney recipients were randomized in a 2:1 fashion to receive tacrolimus or cyclosporine (Sandimmune) in combination with corticosteroids and AZA, but without depletional induction.60 Again, the incidence of acute rejection was significantly lower in the tacrolimus arm at 1 year (25.9% versus 45.7%; P < 0.001) as was corticosteroid-resistant rejection (11.3% versus 21.6%; P = 0.001). At 5 years follow-up, there was less chronic rejection with tacrolimus when compared with cyclosporine, and projected graft half-lives were 15.8 years with FK506 versus 10.8 years for cyclosporine.61 The FDA approved tacrolimus for use in kidney transplantation in 1997 based on these results.

Soon after these registration studies, Sandimmune was replaced by cyclosporine microemulsion (Neoral), a product with more predictable pharmacokinetics that some thought might obviate the perceived advantages of tacrolimus. However, in a large European multicenter randomized trial, BCAR was significantly less common in tacrolimus- (19.6%) than Neoral-treated patients (37.3%) (P < 0.0001). Biopsy-confirmed corticosteroid-resistant rejection was also significantly lower with tacrolimus (27 [9.4%] versus 57 [21.0%]; P < 0.0001). As in previous studies, there were no significant differences in patient or graft survival.

Subsequently, FDA approval in cardiac transplantation was granted in 2006, completing the organ-specific regulatory processes for tacrolimus. By that time, tacrolimus had become the drug of choice (versus cyclosporine) in over 80% of kidney recipients, and virtually all other patients undergoing solid organ transplantation.62

EVOLVING CLINICAL ISSUES IN TACROLIMUS-BASED THERAPY

Tacrolimus and Mycophenolate Mofetil

In 1995, tacrolimus and mycophenolate mofetil (MMF) was approved to prevent acute rejection in kidney transplant recipients, based on evidence generated in 3 randomized, controlled, double-blinded trials that demonstrated superiority over AZA (or placebo) when used with cyclosporine and corticosteroids.63-65 Subsequently, a randomized 3-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare 3 immunosuppressive regimens: tacrolimus + AZA versus cyclosporine (Neoral) + MMF versus tacrolimus + MMF.66 All patients were first deceased-donor kidney recipients, and all regimens included corticosteroids. Similar acute rejection rates and graft survival were noted in each treatment group, but the tacrolimus + MMF regimen was associated with less steroid-resistant rejection.66 Subsequently, results at 3 years showed a particular benefit of the tacrolimus + MMF combination on graft survival in patients who had delayed graft function. Overall, tacrolimus-treated patients had better allograft function.67 This study was also among the first to note that lower doses of MMF were warranted with tacrolimus relative to cyclosporine. It is now well known that cyclosporine inhibits enterohepatic recirculation of mycophenolate and thereby reduces mycophenolic acid (MPA) exposure, an effect not evident with tacrolimus. Thus, similar doses of MMF result in MPA exposure 25%–40% higher with tacrolimus than cyclosporine.68

The ELITE-SYMPHONY study (Efficacy Limiting Toxicity Elimination-Symphony), published in 2007, significantly impacted tacrolimus usage.69 In this trial involving kidney transplant recipients, a regimen of standard-dose cyclosporine, MMF, and corticosteroids was compared with daclizumab induction, MMF, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus (targeted trough levels of 3–7 ng/mL), or low-dose sirolimus (SRL). Contrary to expectation that CNI avoidance would yield better allograft function, the mean calculated glomerular filtration rate (GFR) was higher in patients receiving low-dose tacrolimus (65.4 mL per min) than in the other 3 groups (range, 56.7–59.4 mL per min), with significantly less rejection (12.3% of patients) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose SRL (37.2%). Allograft survival was also highest in the low-dose tacrolimus group (94.2% at 1 y) compared with all the other groups.

In response to these, and other, studies, as well as the predominant role of the off-label use of tacrolimus and MMF in clinical transplantation, the FDA in 2009 approved the combination of these 2 agents, allowing their use as the control immunosuppressive regimen in subsequent clinical trials.70,71 At the same time, the FDA provided more definitive guidelines for both tacrolimus and MMF dosing when used in combination.

Major Drug-specific Toxicities

The short- and long-term toxicity of CNIs had been a concern in the preclinical and clinical studies of cyclosporine, becoming an issue with tacrolimus as well.72 In their pioneering work, Starzl et al acknowledged, “the three major side effects of the drug (nephrotoxicity, neurotoxicity, and diabetogenicity) were comparable to cyclosporine. Hypertension and hyperlipidemia were less than in historical cyclosporine controls, and the cosmetic effects of cyclosporine (hirsutism, gingival hyperplasia, and facial brutalization) had not been seen.”73 Two decades later, these seminal observations have been studied in multiple, specifically designed and often more-focused, clinical studies. The overall more favorable tolerability profile of tacrolimus, beyond prevention of rejection and graft loss, played a significant role in its ascendancy over cyclosporine in clinical practice.74

Cosmetic Side Effects

The cosmetic benefits of tacrolimus over cyclosporine are well established. Gingival hyperplasia, which affects many patients treated with cyclosporine, is not seen with tacrolimus and conversion from cyclosporine to tacrolimus has been used to manage this problem.75,76 Cyclosporine causes hirsutism, whereas tacrolimus is associated with alopecia; patient and clinician preferences generally favor dealing with the latter over the former.77

Hypertension and Hyperlipidemia

Both cyclosporine and tacrolimus are implicated in posttransplant hypertension and hyperlipidemia. Hypertension is ubiquitous in the kidney transplant population and the comparative incidence with cyclosporine versus tacrolimus varies in different clinical trials, dependent on the definition of hypertension as well as CNI dose and concentration, and although arguably less common in patients on tacrolimus, may not in fact differ significantly between the 2 CNIs.69,74,78-81 The mechanism of CNI-induced hypertension has been reviewed elsewhere and has been better studied in cyclosporine than in tacrolimus.82 These mechanisms include renal vasoconstriction, increased sodium retention and in the case of cyclosporine but not tacrolimus, an increased sympathetic tone.83,84 Of note, tacrolimus has been shown to activate the renal sodium chloride cotransporter, and the inhibition of sodium chloride cotransporter with a thiazide diuretic may be especially effective in treating tacrolimus-induced hypertension.85,86 Most studies indicate more favorable lipid profiles with tacrolimus than cyclosporine.74,81,87 In hyperlipidemic patients, the relative lack of drug-drug interaction between statins and tacrolimus (versus cyclosporine) eases management.88-90

Neurotoxicity

Neurotoxicity, with tendencies to headache, tremor, insomnia, and paresthesia, is common with tacrolimus and was also recognized from its earliest use by Starzl et al.91 More severe symptoms are fortunately rare but include seizures, delirium, cortical blindness, and encephalopathy, including the posterior reversible encephalopathy syndrome.92-97 The mechanism of CNI neurotoxicity is uncertain and has been hypothesized to be related to CNI-induced disruption of the blood brain barrier, leading to vasogenic edema and apoptosis.98,99 The incidence of CNI neurotoxicity is higher with tacrolimus versus cyclosporine and may improve with a reduction in dose or substitution with cyclosporine or non-CNI immunosuppression.74,100 Intriguingly, the results of the STRATO study (n = 38) indicated that switching from immediate-release tacrolimus (IR-tac) to once daily LCP-tacrolimus, which has a lower drug peak, decreased tremors as measured by blinded neurologists and by accelerometer readings.101

Diabetogenicity

NODAT is common. In precyclosporine days, NODAT was termed “steroid-induced diabetes” and a 2013 international consensus meeting has suggested that this terminology be changed to posttransplant diabetes mellitus (PTDM).102 PTDM became of greater concern after the introduction of cyclosporine, shown to reduce islet function in rodents at therapeutic doses.103 Likewise, tacrolimus is toxic to pancreatic islet cells in vitro and in vivo.104,105 In the comparative clinical trials noted above, PTDM was typically more common with tacrolimus than cyclosporine.57,60 In a tightly controlled, randomized, prospective clinical trial involving 567 nondiabetic kidney recipients (the DIRECT trial), PTDM or impaired fasting glucose was noted in 33% of tacrolimus-treated patients and also in 26% of those on cyclosporine (P = 0.046) but with no significant difference in short-term clinical outcomes.106 In practice, minimization or avoidance of corticosteroids has proven efficacious in reducing the frequency or severity of PTDM.107,108 Additionally, in a remarkable turn of events, recent scientific registry of transplant recipients (SRTR) data indicate a profound decline in PTDM frequency in recent years, despite ubiquitous and ongoing use of tacrolimus109 (Figure 2). This finding of a temporal decrease in PTDM rates has also been noticed in a series of studies from a single center in Norway, where using the WHO OGTT criteria, PTDM rates have dropped from 18% in 1995, 13% in 2005, and 11% in 2012, in spite of increased tacrolimus use.110-112 The decline in PTDM in this series of studies was attributed by the authors to decreased steroid use, lower rates of rejection, and better management of Cytomegalovirus infection and disease. Conversion from twice daily tacrolimus to once daily tacrolimus (ER-tacrolimus) has been studied in stable transplant patients with a possible short-term benefit in insulin secretion and better glycemic control but lowered risk of PTDM has not been seen in larger studies nor in a metaanalysis.113-116

F2
FIGURE 2.:
Posttransplant diabetes, from SRTR report 2017. SRTR, scientific registry of transplant recipients.

Nephrotoxicity

From its earliest use in humans, cyclosporine was known to be nephrotoxic. Coincident with its approval by the FDA in 1983 was a prominent publication reporting severe nephrotoxicity in cardiac transplant recipients.9,72 Over the next 2 decades, increasing use of cyclosporine was offset by myriad strategies to minimize cyclosporine exposure to minimize or limit nephrotoxicity. These included delayed administration (antibody induction), addition of AZA to enable dose reduction, long-term dose minimization, and addition of various agents to the regimen to provide renal protection.

By 2003, the immunosuppressive efficacy of transplant drug regimens, enhanced by availability of tacrolimus and MMF after the mid-1990s, was thought to be so great that immunologic graft loss had become uncommon.117 Associated with these observations was recognition that improvements in renal allograft survival had been primarily in the first posttransplant year, without commensurate increments in late graft survival.118 Kidney half-life in recipients of deceased-donor transplants was 6.6 years in 1989, 8 years in 1995, but only 8.8 years by 2005. In low-risk populations like living-donor-recipients half-life did not change: 11.4 years in 1989 and 11.9 years in 2005.119 In 2003, Nankivell et al117 from Westmeade reported that in follow-up surveillance biopsies of 110 kidney-pancreas transplants, changes then thought to be due to calcineurin-inhibitor (CNI) toxicity (arteriolar hyalinosis, ischemic glomerulosclerosis, and interstitial fibrosis) were nearly ubiquitous after 5–10 years, and felt likely to be the principal cause of late graft failure. The same year, in another prominent article, Ojo et al120 noted the relatively high frequency of chronic renal failure in solid organ transplant recipients and attributed it largely to CNI nephrotoxicity. The overwhelming majority of patients in both series had been treated with cyclosporine.

Several studies, along with prevailing clinical impressions, supported tacrolimus as less nephrotoxic than cyclosporine.80,121 In ELITE-SYMPHONY, estimated GFR remained higher in the tacrolimus-treated patients out to 3 years posttransplant, a group that also experienced substantially less rejection.69 In a subsequent histology-based study, the Westmeade group noted that tacrolimus-based therapy in kidney-pancreas transplants resulted in less early CNI toxicity and less interstitial fibrosis, but rates of arteriolar hyalinosis similar to cyclosporine.122 Most recently, late graft failure has been increasingly attributed to chronic antibody-mediated injury, a mechanism not well established by 2003 and likely a manifestation of under immunosuppression.123 In addition, the nonspecific histologic lesions noted above and previously attributed to CNI toxicity are not only present in patients never on cyclosporine or tacrolimus but also attributable to the presence of donor-specific antibodies.124,125

Afferent arteriolar hyalinosis, long felt to be a hallmark of CNI nephrotoxicity, may in fact indicate adequate CNI exposure when other factors such as donor age and time of biopsy after transplant are taken into account and the unexpected absence of arteriolar hyalinosis lesions in for cause biopsies is associated with increased frequency of T-cell mediated rejection (TCMR) and graft loss.126 Most recent results from Nankivell et al127 in their cohort of kidney-pancreas patients have linked serial kidney biopsy findings of acute and subclinical TCMR to subsequent findings of inflammation within areas of interstitial fibrosis and tubular atrophy (i-IFTA). i-IFTA in turn may contribute to poorer graft function and histologic progression to chronic fibrosis. TCMR and i-IFTA were both reduced, with less chronic fibrosis and better graft function, in the current tacrolimus era. Thus, although CNI nephrotoxicity as an entity remains a concern in clinical practice, its long-term causes and consequences are now much more difficult to interpret.

Novel Immunosuppressant Combinations

The challenge of administering effective, nonnephrotoxic immunosuppression persists. As in the cyclosporine era, numerous clinical strategies to reduce or avoid CNI exposure have emerged, the most promising of which involve using the mammalian target of rapamycin (mTOR) inhibitors and belatacept, a T-cell costimulation blocker.

A new class of immunosuppressants emerged on the scene with FDA approval of SRL, an mTOR inhibitor thought not to be nephrotoxic, in 1998. In the CONVERT trial, 830 renal allograft recipients, 6–120 months posttransplant and receiving cyclosporine or tacrolimus, were randomly assigned to continue the CNI (n = 275) or switch to SRL (n = 555).128 Enrollment of patients with GFR 20–40 mL/min group was halted early because of a higher incidence of the primary end point of acute rejection, graft loss or death in patients on SRL. Overall, intent-to-treat analyses at 12 and 24 months showed no significant difference among groups if GFR at conversion was ≥40 mL/min. A significant number of patients were unable to tolerate SRL because of worsening proteinuria or other adverse effects. Patients able to remain on SRL showed significantly higher GFR at 12 and 24 months. Rates of BCAR, graft survival, and patient survival were similar between groups. Malignancy rates, particularly nonmelanoma skin cancers, were lower in successfully converted patients. Overall, a convincing case could not be made for late SRL conversion.

In the ORION study, 2 SRL-based regimens (groups 1 and 2) were compared with tacrolimus and MMF (group 3).129 Group 1 started with both SRL and tacrolimus, eliminating the latter by week 13. Group 2 avoided tacrolimus altogether. Recruitment into group 2 was terminated early because of higher than expected BCAR. Graft survival was best in group 3, with BCAR also lowest in this group. As with the CONVERT trial, a significant number of patients were unable to tolerate the adverse effects of SRL renal function at 1- and 2-years (modified intent-to-treat) was similar. A larger number of patients in the SRL arms stopped the study drug primarily because of adverse events (group 1, 34.2%; group 2, 33.6%; group 3, 22.3%; P < 0.05). It was also noted that in the SRL groups, delayed wound healing and hyperlipidemia were more frequent. One-year post hoc analysis of new-onset diabetes posttransplantation was greater in recipients receiving tacrolimus (groups 1 and 3 versus 2; 17% versus 6%; P = 0.004). Malignancy rates were similar. The investigators concluded that SRL-based regimens were not associated with improved outcomes for kidney recipients.

Everolimus (EVR), an analogue of SRL with superior oral bioavailability, was developed in 1997 and obtained FDA approval in 2010.130 EVR has been studied in CNI sparing and CNI-minimizing regimens, primarily with cyclosporine as a comparator, both in conversion trials and in de novo renal transplants.131-137 Results of these studies largely mirrored outcomes with SRL, with better GFR in EVR-treated patients but at a cost of higher rates of rejection, adverse events, and drug discontinuation. The results of combining EVR with a CNI-minimization strategy using low-dose cyclosporine have been encouraging, avoiding the adverse effects of high mTOR levels and maintaining adequate immunosuppression while perhaps reaping benefits of lesser CNI exposure.138,139

In the TRANSFORM trial, a randomized international trial in 2037 de novo kidney transplant recipients, the combination of EVR (targeted trough 3–8 ng/mL), with low-dose tacrolimus or cyclosporine was found to be noninferior for a combined end point of biopsy-proven rejection or estimated GFR <50 mL/min per 1.73 m2 when compared with standard therapy with tacrolimus and MPA.140 De novo donor-specific antibody (DSA) and incidence of antibody-mediated rejection did not differ between the 2 arms, with fewer Cytomegalovirus and BK infections in the EVR arm. As in previous mTOR studies, a higher percentage of EVR-treated patients (23% versus 11.9%) discontinued the study drug because of adverse effects.141 The TRANSFORM trial provides evidence for a viable option to the current mainstay of tacrolimus with MPA but long-term follow-up is needed to assess effects on malignancy and cardiovascular events.

Belatacept, a fusion protein that prevents T-cell costimulation by binding to CD80/86, was developed in a series of clinical trials with control groups receiving cyclosporine rather than tacrolimus.142,143 The BENEFIT trial compared 2 regimens of belatacept with cyclosporine in 2 cohorts of kidney transplant recipients defined by donor quality. In both studies, belatacept-treated patients demonstrated better renal function, but similar graft and patient survival and more early acute rejection.144,145 In the belatacept early steroid withdrawal trial (BEST) trial, kidney transplant recipients were randomized to receive alemtuzumab/belatacept, or rabbit antithymocyte globulin/belatacept, or rabbit antithymocyte globulin/ tacrolimus with rapid early corticosteroid withdrawal.146 Although only 1y results are available, the belatacept-based regimens were not associated with better GFRs. However, as in BENEFIT, the BEST trial demonstrated higher rates of biopsy-confirmed acute cellular rejection in the belatacept-treated patients, but not antibody-mediated or mixed acute rejection. A recent single-center report indicates a transient course of tacrolimus, along with maintenance belatacept can be adopted successfully as a strategy to avoid the early rejection seen in BENEFIT.147

The Clinical Trials in Transplantation-09 tested the hypothesis that, in a select subgroup of patients, tacrolimus could be safely stopped after transplantation.148 In this trial, kidney recipients received rabbit antithymocyte globulin, tacrolimus, MMF, and prednisone. At 6 months posttransplantation, those with pristine courses, without de novo DSAs, and benign surveillance biopsy findings were randomized to wean off or remain on tacrolimus. The study was terminated early because of unacceptable rates of acute rejection (4 of 14) and de novo DSAs (5 of 14) in the tacrolimus-withdrawal arm. The authors concluded that complete CNI withdrawal should be strongly discouraged, even in those who are deemed to be immunologically quiescent based on existing scientific knowledge.

Operational tolerance, the absence of rejection without immunosuppression, has been a long held goal in organ transplantation.149 Regulatory T cells (Treg) are known to play an important role in suppressing immune responses.150 The CNIs, tacrolimus and cyclosporine, inhibit nuclear factor of activated T cells and exert a negative effect not just on effector T cells but also on Treg and effective ways to promote Treg survival may influence the development of future immunosuppressive regimens.151-153

BEYOND PROGRAF

Until 2008, branded Prograf was the only tacrolimus preparation available. In subsequent years, generics have become available with trial data and metaanalyses indicating bioequivalence with branded drug.154-157 However, criticism persists: the approval process is based on pharmacokinetic studies in healthy volunteers rather than transplant recipients, may not address certain risk groups (pediatric and African American patients), and bioequivalence between generic and brand product may not equate to bioequivalence among generics.158-160 Standards for what constitutes bioequivalence also differ among regulatory bodies,161-163 and issues of patient perception and acceptance, which may vary with income, ethnicity, and prior experience with generics are not well understood.164 As the use of generic tacrolimus has multiplied, most centers at least attempt to monitor drug levels more closely after a change in drug formulation.165

Once daily formulations of tacrolimus have been developed by Astellas (ER-tacrolimus, Astagraf XL in the USA, Advagraf in Europe) and by Veloxis (LCP-tacrolimus, Envarsus XR). In conversion and de novo trials, both drugs have been shown to be noninferior to twice daily tacrolimus (IR-tacrolimus).166-169 Prolonged drug release with ER-tacrolimus is achieved by the addition of ethylcellulose whereas with LCP-tacrolimus, this is achieved with MeltDose technology that increases drug solubility and hence bioavailability. Not surprisingly, ER-tacrolimus and LCP-tacrolimus have different pharmacokinetics. In a PK study of ER-tacrolimus, LCP-tacrolimus, and IR-tacrolimus, LCP-tacrolimus had a longer time to peak concentration, lower peak concentration and higher AUC0-24 and lower intraday fluctuation when compared with the other preparations.170 (Figure 3) ER-tacrolimus had a similar time to peak concentration but a lower Cmin and AUC0-24 compared with IR-tacrolimus. Based on this study, the authors suggested a dose adjustment of −30% when converting from IR-tacrolimus to LCP-tacrolimus and a dose increase of 8% when converting from IR to ER-tacrolimus, which is at variance with the drug manufacturer recommendations of a 1:1 conversion ratio for ER-tacrolimus/IR-tacrolimus and 0.8:1 conversion ratio for LCP-tacrolimus/IR-tacrolimus. Long-term studies using ER-tacrolimus have also suggested that an increased dose is required to maintain drug Cmin and AUC0-24 when compared with IR-tacrolimus.171-173 A benefit of a lower Cmax with LCP-tacrolimus may be a reduction in neurological side effects; and as mentioned in an earlier section of our paper, patients with tremors noted clinical improvement when switched from IR-tacrolimus.101 Additionally, use of ER-tacrolimus may increase patient adherence.174 In clinical trials and clinical practice, the target 24-hour trough levels with once daily tacrolimus do not differ from the twice daily formulations.169,175

F3
FIGURE 3.:
Drug concentration curves for IR-tacrolimus, ER-tacrolimus, and LCP-tacrolimus, from Tremblay et al. AUC, area under the blood concentration time curve.

Quo Vadis

In a quarter century of widespread clinical usage, tacrolimus has become an essential component of successful transplant outcomes for innumerable solid organ transplant recipients. In most of the world, across heart, lung, kidney, liver, and pancreas, tacrolimus is standard of care whether combined with mycophenolate, mTOR inhibitors, corticosteroids, or other agents. Despite a plethora of novel therapeutics that have come along (and disappeared) since the early 1990s in attempts to supplant tacrolimus, none have broadly succeeded as yet. Certainly, dealing with adverse effects of tacrolimus remains a vexing problem for patients and practitioners alike, and at some point, a novel approach (whether a better immunosuppressant or clinical management without immunosuppression) may succeed.176-178 In the meantime, as we enter a new decade, we remain squarely in the tacrolimus era, grateful that, despite its drawbacks, life-saving outcomes are the norm for so many transplanted patients.179

REFERENCES

1. Starzl TE, Todo S, Fung J, et al. FK 506 for liver, kidney, and pancreas transplantation. Lancet. 1989; 2:1000–1004. doi:10.1016/s0140-6736(89)91014-3
2. Merrill JP, Murray JE, Harrison JH, et al. Successful homotransplantation of the human kidney between identical twins. J Am Med Assoc. 1956; 160:277–282. doi:10.1001/jama.1956.02960390027008
3. Mannick JA, Davis RC, Cooperband SR, et al. Clinical use of rabbit antihuman lymphocyte globulin in cadaver-kidney transplantation. N Engl J Med. 1971; 284:1109–1115. doi:10.1056/NEJM197105202842001
4. Doak PB, Dalton NT, Meredith J, et al. Use of antilymphocyte globulin after cadaveric renal transplantation. Br Med J. 1969; 4:522–525. doi:10.1136/bmj.4.5682.522
5. Starzl TE, Marchioro TL, Porter KA, et al. Homotransplantation of the liver. Transplantation. 1967; 5(Suppl):790–803. doi:10.1097/00007890-196707001-00003
6. Murray JE, Merrill JP, Harrison JH, et al. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N Engl J Med. 1963; 268:1315–1323. doi:10.1056/NEJM196306132682401
7. Calne RY. The rejection of renal homografts. Inhibition in dogs by 6-mercaptopurine. Lancet. 1960; 1:417–418. doi:10.1016/s0140-6736(60)90343-3
8. Starzl TE, Marchioro TL, Brittain RS, et al. Problems in renal homotransplantation. JAMA. 1964; 187:734–740. doi:10.1001/jama.1964.03060230062016
9. Calne RY, White DJ, Thiru S, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet. 1978; 2:1323–1327. doi:10.1016/s0140-6736(78)91970-0
10. 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; 2:1033–1036. doi:10.1016/s0140-6736(79)92440-1
11. Starzl TE, Weil R III, Iwatsuki S, et al. The use of cyclosporin A and prednisone in cadaver kidney transplantation. Surg Gynecol Obstet. 1980; 151:17–26.
12. Calne RY, Rolles K, White DJ, et al. Cyclosporin A in organ transplantation. Adv Nephrol Necker Hosp. 1981; 10:335–347.
13. 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; 6:637–640. doi:10.1007/BF01657885
14. Ferguson RM, Rynasiewicz JJ, Sutherland DE, et al. Cyclosporin A in renal transplantation: a prospective randomized trial. Surgery. 1982; 92:175–182.
15. Hamilton DV, Calne RY, Evans DB. Hemolytic-uraemic syndrome and cyclosporin A. Lancet. 1982; 2:151–152. doi:10.1016/s0140-6736(82)91111-4
16. Squifflet JP, Sutherland DE, Rynasiewicz JJ, et al. Combined immunosuppressive therapy with cyclosporin A and azathioprine. A synergistic effect in three of four experimental models. Transplantation. 1982; 34:315–318. doi:10.1097/00007890-198212000-00001
17. Simmons RL, Canafax DM, Strand M, et al. Management and prevention of cyclosporine nephrotoxicity after renal transplantation: use of low doses of cyclosporine, azathioprine, and prednisone. Transplant Proc. 1985; 17(Suppl 1):266–275.
18. Sutherland DE, Fryd DS, Strand MH, et al. Results of the Minnesota randomized prospective trial of cyclosporine versus azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients. Am J Kidney Dis. 1985; 5:318–327. doi:10.1016/s0272-6386(85)80161-x
19. Hariharan S, Johnson CP, Bresnahan BA, et al. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000; 342:605–612. doi:10.1056/NEJM200003023420901
20. Starzl TE, Klintmalm GB, Porter KA, et al. Liver transplantation with use of cyclosporin a and prednisone. N Engl J Med. 1981; 305:266–269. doi:10.1056/NEJM198107303050507
21. Jain A, Reyes J, Kashyap R, et al. Long-term survival after liver transplantation in 4,000 consecutive patients at a single center. Ann Surg. 2000; 232:490–500. doi:10.1097/00000658-200010000-00004
22. Hosenpud JD, Novick RJ, Breen TJ, et al. The registry of the International Society for Heart and Lung Transplantation: twelfth official report–1995. J Heart Lung Transplant. 1995; 14:805–815.
23. Kino T, Inamura N, Sakai F, et al. Effect of FK-506 on human mixed lymphocyte reaction in vitro. Transplant Proc. 1987; 19(Suppl 6):36–39.
24. Ochiai T, Nagata M, Nakajima K, et al. Effects of FK-506 on xenotransplantation of the heart and skin in a mouse-rat combination. Transplant Proc. 1987; 19(Suppl 6):84–86.
25. Ochiai T, Nagata M, Nakajima K, et al. Prolongation of canine renal allograft survival by treatment with FK-506. Transplant Proc. 1987; 19(Suppl 6):53–56.
26. Ochiai T, Nagata M, Nakajima K, et al. Studies of the effects of FK506 on renal allografting in the beagle dog. Transplantation. 1987; 44:729–733. doi:10.1097/00007890-198712000-00001
27. Ochiai T, Nakajima K, Nagata M, et al. Studies of the induction and maintenance of long-term graft acceptance by treatment with FK506 in heterotopic cardiac allotransplantation in rats. Transplantation. 1987; 44:734–738. doi:10.1097/00007890-198712000-00002
28. Murase N, Todo S, Lee PH, et al. Heterotopic heart transplantation in the rat receiving FK-506 alone or with cyclosporine. Transplant Proc. 1987; 19(Suppl 6):71–75.
29. Todo S, Demetris AJ, Ueda Y, et al. Canine kidney transplantation with FK-506 alone or in combination with cyclosporine and steroids. Transplant Proc. 1987; 19(Suppl 6):57–61.
30. Liu J, Farmer JD Jr, Lane WS, et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991; 66:807–815. doi:10.1016/0092-8674(91)90124-H
31. Venkataramanan R, Jain A, Warty VW, et al. Pharmacokinetics of FK 506 following oral administration: a comparison of FK 506 and cyclosporine. Transplant Proc. 1991; 23(1 Pt 2):931–933.
32. Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part I. Clin Pharmacokinet. 2010; 49:141–175. doi:10.2165/11317350-000000000-00000
33. Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part II. Clin Pharmacokinet. 2010; 49:207–221. doi:10.2165/11317550-000000000-00000
34. Hesselink DA, van Schaik RH, van der Heiden IP, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther. 2003; 74:245–254. doi:10.1016/S0009-9236(03)00168-1
35. Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995; 29:404–430. doi:10.2165/00003088-199529060-00003
36. Bekersky I, Dressler D, Mekki Q. Effect of time of meal consumption on bioavailability of a single oral 5 mg tacrolimus dose. J Clin Pharmacol. 2001; 41:289–297. doi:10.1177/00912700122010104
37. Lemahieu W, Maes B, Verbeke K, et al. Cytochrome P450 3A4 and P-glycoprotein activity and assimilation of tacrolimus in transplant patients with persistent diarrhea. Am J Transplant. 2005; 5:1383–1391. doi:10.1111/j.1600-6143.2005.00844.x
38. Tamura K, Kobayashi M, Hashimoto K, et al. A highly sensitive method to assay FK-506 levels in plasma. Transplant Proc. 1987; 19(Suppl 6):23–29.
39. Starzl TE, Fung J, Jordan M, et al. Kidney transplantation under FK 506. JAMA. 1990; 264:63–67.
40. Boswell GW, Bekersky I, Fay J, et al. Tacrolimus pharmacokinetics in BMT patients. Bone Marrow Transplant. 1998; 21:23–28. doi:10.1038/sj.bmt.1701054
41. Christians U, Jacobsen W, Benet LZ, et al. Mechanisms of clinically relevant drug interactions associated with tacrolimus. Clin Pharmacokinet. 2002; 41:813–851. doi:10.2165/00003088-200241110-00003
42. Borra LC, Roodnat JI, Kal JA, et al. High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation. Nephrol Dial Transplant. 2010; 25:2757–2763. doi:10.1093/ndt/gfq096
43. Sapir-Pichhadze R, Wang Y, Famure O, et al. Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure. Kidney Int. 2014; 85:1404–1411. doi:10.1038/ki.2013.465
44. Hsiau M, Fernandez HE, Gjertson D, et al. Monitoring nonadherence and acute rejection with variation in blood immunosuppressant levels in pediatric renal transplantation. Transplantation. 2011; 92:918–922. doi:10.1097/TP.0b013e31822dc34f
45. Rodrigo E, Segundo DS, Fernández-Fresnedo G, et al. Within-patient variability in tacrolimus blood levels predicts kidney graft loss and donor-specific antibody development. Transplantation. 2016; 100:2479–2485. doi:10.1097/TP.0000000000001040
46. van Gelder T. Within-patient variability in immunosuppressive drug exposure as a predictor for poor outcome after transplantation. Kidney Int. 2014; 85:1267–1268. doi:10.1038/ki.2013.484
47. Todo S, Fung JJ, Starzl TE, et al. Liver, kidney, and thoracic organ transplantation under FK 506. Ann Surg. 1990; 212:295307–305discussion 306. doi:10.1097/00000658-199009000-00008
48. Todo S, Fung JJ, Starzl TE, et al. Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression. Ann Surg. 1994; 220:297309–308discussion 308. doi:10.1097/00000658-199409000-00006
49. Fung JJ, Eliasziw M, Todo S, et al. The Pittsburgh randomized trial of tacrolimus compared to cyclosporine for hepatic transplantation. J Am Coll Surg. 1996; 183:117–125.
50. Thomas E; The Official Dr. Starzl Website at the University of Pittsburg. Available at https://www.starzl.pitt.edu/. Accessed January 1, 2020.
51. Starzl TE, Iwatsuki S, Shaw BW Jr, et al. Consensus conference report on liver* transplantation. Dializ Transplant Yanik. 1983; 1:27–32.
52. OPTN Data Reports. Available at https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/#. Accessed December 29, 2019.
53. Starzl TE, Donner A, Eliasziw M, et al. Randomised trialomania? The multicentre liver transplant trials of tacrolimus. Lancet. 1995; 346:1346–1350.
54. U.S. Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med. 1994; 331:1110–1115. doi:10.1056/NEJM199410273311702
55. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Lancet. 1994; 344:423–428.
56. Vincenti F, Laskow DA, Neylan JF, et al. One-year follow-up of an open-label trial of FK506 for primary kidney transplantation. A report of the U.S. Multicenter FK506 Kidney Transplant Group. Transplantation. 1996; 61:1576–1581. doi:10.1097/00007890-199606150-00005
57. Pirsch JD, Miller J, Deierhoi MH, et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation. 1997; 63:977–983. doi:10.1097/00007890-199704150-00013
58. Jensik SC. Tacrolimus (FK 506) in kidney transplantation: three-year survival results of the US multicenter, randomized, comparative trial. FK 506 Kidney Transplant Study Group. Transplant Proc. 1998; 30:1216–1218. doi:10.1016/s0041-1345(98)00216-4
59. Vincenti F. Tacrolimus (FK 506) in kidney transplantation: five-year survival results of the U.S. multicenter, randomized, comparative trial. Transplant Proc. 2001; 33:1019–1020. doi:10.1016/s0041-1345(00)02312-5
60. Mayer AD, Dmitrewski J, Squifflet JP, et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation. 1997; 64:436–443. doi:10.1097/00007890-199708150-00012
61. Mayer AD. Chronic rejection and graft half-life: five-year follow-up of the European Tacrolimus Multicenter Renal Study. Transplant Proc. 2002; 34:1491–1492. doi:10.1016/s0041-1345(02)02942-1
62. SRTR/OPTN Annual Data Report 2006 2006.
63. Mycophenolate mofetil in renal transplantation: 3-year results from the placebo-controlled trial. European Mycophenolate Mofetil Cooperative Study Group. Transplantation. 1999; 68:391–396.
64. Mathew TH. A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation. 1998; 65:1450–1454. doi:10.1097/00007890-199806150-00007
65. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation. 1995; 60:225–232. doi:10.1097/00007890-199508000-00003
66. 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; 69:834–841. doi:10.1097/00007890-200003150-00028
67. Gonwa T, Johnson C, Ahsan N, et al. Randomized trial of tacrolimus + mycophenolate mofetil or azathioprine versus cyclosporine + mycophenolate mofetil after cadaveric kidney transplantation: results at three years. Transplantation. 2003; 75:2048–2053. doi:10.1097/01.TP.0000069831.76067.22
68. Gaston RS, Kaplan B, Shah T, et al. Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: the Opticept trial. Am J Transplant. 2009; 9:1607–1619. doi:10.1111/j.1600-6143.2009.02668.x
69. Ekberg H, Tedesco-Silva H, Demirbas A, et al.; ELITE-Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007; 357:2562–2575. doi:10.1056/NEJMoa067411
70. Vincenti F, Klintmalm G, Halloran PF. Open letter to the FDA: new drug trials must be relevant. Am J Transplant. 2008; 8:733–734. doi:10.1111/j.1600-6143.2007.02122.x
71. FDA approval for the use tacrolimus with mycophenolate mofetil in kidney transplantation. Available at https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/050708s027,050709s021ltr.pdf. Published 2009. Accessed 3 May 2020.
72. Myers BD, Ross J, Newton L, et al. Cyclosporine-associated chronic nephropathy. N Engl J Med. 1984; 311:699–705. doi:10.1056/NEJM198409133111103
73. Starzl TE, Todo S, Demetris AJ, et al. Tacrolimus (FK506) and the pharmaceutical/academic/regulatory gauntlet. Am J Kidney Dis. 1998; 31(Suppl 1):S7–S14. doi:10.1053/ajkd.1998.v31.pm9631858
74. Webster AC, Woodroffe RC, Taylor RS, et al. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ. 2005; 331:810. doi:10.1136/bmj.38569.471007.AE
75. Seymour RA, Jacobs DJ. Cyclosporin and the gingival tissues. J Clin Periodontol. 1992; 19:1–11. doi:10.1111/j.1600-051x.1992.tb01140.x
76. James JA, Boomer S, Maxwell AP, et al. Reduction in gingival overgrowth associated with conversion from cyclosporin A to tacrolimus. J Clin Periodontol. 2000; 27:144–148. doi:10.1034/j.1600-051x.2000.027002144.x
77. Tricot L, Lebbé C, Pillebout E, et al. Tacrolimus-induced alopecia in female kidney-pancreas transplant recipients. Transplantation. 2005; 80:1546–1549. doi:10.1097/01.tp.0000181195.67084.94
78. Klein IH, Abrahams A, van Ede T, et al. Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects. Transplantation. 2002; 73:732–736. doi:10.1097/00007890-200203150-00012
79. Krämer BK, Del Castillo D, Margreiter R, et al.; European Tacrolimus versus Ciclosporin Microemulsion Renal Transplantation Study Group. Efficacy and safety of tacrolimus compared with ciclosporin A in renal transplantation: three-year observational results. Nephrol Dial Transplant. 2008; 23:2386–2392. doi:10.1093/ndt/gfn004
80. Vincenti F, Jensik SC, Filo RS, et al. A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation. 2002; 73:775–782. doi:10.1097/00007890-200203150-00021
81. Morales JM, Domínguez-Gil B. Impact of tacrolimus and mycophenolate mofetil combination on cardiovascular risk profile after kidney transplantation. J Am Soc Nephrol. 2006; 17(Suppl 3):S296–S303. doi:10.1681/ASN.2006080930
82. Hoorn EJ, Walsh SB, McCormick JA, et al. Pathogenesis of calcineurin inhibitor-induced hypertension. J Nephrol. 2012; 25:269–275. doi:10.5301/jn.5000174
83. Gardiner SM, March JE, Kemp PA, et al. Regional haemodynamic effects of cyclosporine A, tacrolimus and sirolimus in conscious rats. Br J Pharmacol. 2004; 141:634–643. doi:10.1038/sj.bjp.0705659
84. Klein IH, Abrahams AC, van Ede T, et al. Differential effects of acute and sustained cyclosporine and tacrolimus on sympathetic nerve activity. J Hypertens. 2010; 28:1928–1934. doi:10.1097/HJH.0b013e32833c20eb
85. Hoorn EJ, Walsh SB, McCormick JA, et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nat Med. 2011; 17:1304–1309. doi:10.1038/nm.2497
86. Moes AD, Hesselink DA, van den Meiracker AH, et al. Chlorthalidone versus amlodipine for hypertension in kidney transplant recipients treated with tacrolimus: a randomized crossover trial. Am J Kidney Dis. 2017; 69:796–804. doi:10.1053/j.ajkd.2016.12.017
87. Margreiter R. European Tacrolimus vs Ciclosporin Microemulsion Renal Transplantation Study Group. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study. Lancet. 2002; 359:741–746. doi:10.1016/S0140-6736(02)07875-3
88. Gaston RS, Kasiske BL, Fieberg AM, et al. Use of cardioprotective medications in kidney transplant recipients. Am J Transplant. 2009; 9:1811–1815. doi:10.1111/j.1600-6143.2009.02696.x
89. Lemahieu WP, Hermann M, Asberg A, et al. Combined therapy with atorvastatin and calcineurin inhibitors: no interactions with tacrolimus. Am J Transplant. 2005; 5:2236–2243. doi:10.1111/j.1600-6143.2005.01005.x
90. Lemahieu WP, Maes BD, Verbeke K, et al. CYP3A4 and P-glycoprotein activity in healthy controls and transplant patients on cyclosporin vs. tacrolimus vs. sirolimus. Am J Transplant. 2004; 4:1514–1522. doi:10.1111/j.1600-6143.2004.00539.x
91. Eidelman BH, Abu-Elmagd K, Wilson J, et al. Neurologic complications of FK 506. Transplant Proc. 1991; 23:3175–3178.
92. Chopra A, Kolla BP, Mansukhani MP, et al. Valproate-induced hyperammonemic encephalopathy: an update on risk factors, clinical correlates and management. Gen Hosp Psychiatry. 2012; 34:290–298. doi:10.1016/j.genhosppsych.2011.12.009
93. Scheel AK, Blaschke S, Schettler V, et al. Severe neurotoxicity of tacrolimus (FK506) after renal transplantation: two case reports. Transplant Proc. 2001; 33:3693–3694. doi:10.1016/s0041-1345(01)02506-4
94. Wijdicks EF, Wiesner RH, Dahlke LJ, et al. FK506-induced neurotoxicity in liver transplantation. Ann Neurol. 1994; 35:498–501. doi:10.1002/ana.410350422
95. Cakmak F, Kanbakan A, Akdeniz YS, et al. Tacrolimus-induced vision loss in a renal transplant patient: posterior reversible encephalopathy syndrome. Exp Clin Transplant. 2019. doi:10.6002/ect.2018.0193
96. Hodnett P, Coyle J, O’Regan K, et al. PRES (posterior reversible encephalopathy syndrome), a rare complication of tacrolimus therapy. Emerg Radiol. 2009; 16:493–496. doi:10.1007/s10140-008-0782-6
97. Kiemeneij IM, de Leeuw FE, Ramos LM, et al. Acute headache as a presenting symptom of tacrolimus encephalopathy. J Neurol Neurosurg Psychiatry. 2003; 74:1126–1127. doi:10.1136/jnnp.74.8.1126
98. Wijdicks EF. Neurotoxicity of immunosuppressive drugs. Liver Transpl. 2001; 7:937–942. doi:10.1053/jlts.2001.27475
99. Zhang W, Egashira N, Masuda S. Recent topics on the mechanisms of immunosuppressive therapy-related neurotoxicities. Int J Mol Sci. 2019; 20:3210. doi:10.3390/ijms20133210
100. Böttiger Y, Brattström C, Tydén G, et al. Tacrolimus whole blood concentrations correlate closely to side-effects in renal transplant recipients. Br J Clin Pharmacol. 1999; 48:445–448. doi:10.1046/j.1365-2125.1999.00007.x
101. Langone A, Steinberg SM, Gedaly R, et al.; STRATO Investigators. Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study. Clin Transplant. 2015; 29:796–805. doi:10.1111/ctr.12581
102. Sharif A, Hecking M, de Vries AP, et al. Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions. Am J Transplant. 2014; 14:1992–2000. doi:10.1111/ajt.12850
103. Yale JF, Roy RD, Grose M, et al. Effects of cyclosporine on glucose tolerance in the rat. Diabetes. 1985; 34:1309–1313. doi:10.2337/diab.34.12.1309
104. Johnson JD, Ao Z, Ao P, et al. Different effects of FK506, rapamycin, and mycophenolate mofetil on glucose-stimulated insulin release and apoptosis in human islets. Cell Transplant. 2009; 18:833–845. doi:10.3727/096368909X471198
105. Soleimanpour SA, Crutchlow MF, Ferrari AM, et al. Calcineurin signaling regulates human islet {beta}-cell survival. J Biol Chem. 2010; 285:40050–40059. doi:10.1074/jbc.M110.154955
106. Vincenti F, Friman S, Scheuermann E, et al.; DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C Monitoring Versus Tacrolimus) Investigators. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant. 2007; 7:1506–1514. doi:10.1111/j.1600-6143.2007.01749.x
107. Woodle ES, First MR, Pirsch J, et al.; Astellas Corticosteroid Withdrawal Study Group. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg. 2008; 248:564–577. doi:10.1097/SLA.0b013e318187d1da
108. Serrano OK, Kandaswamy R, Gillingham K, et al. Rapid discontinuation of prednisone in kidney transplant recipients: 15-year outcomes from the University of Minnesota. Transplantation. 2017; 101:2590–2598. doi:10.1097/TP.0000000000001756
109. Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2017 annual data report: kidney. Am J Transplant. 2019; 19((Suppl 2):19–123. doi:10.1111/ajt.15274
110. Hjelmesaeth J, Hartmann A, Kofstad J, et al. Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age. Transplantation. 1997; 64:979–983. doi:10.1097/00007890-199710150-00008
111. Valderhaug TG, Hjelmesaeth J, Rollag H, et al. Reduced incidence of new-onset posttransplantation diabetes mellitus during the last decade. Transplantation. 2007; 84:1125–1130. doi:10.1097/01.tp.0000287191.45032.38
112. von Düring ME, Jenssen T, Bollerslev J, et al. Visceral fat is better related to impaired glucose metabolism than body mass index after kidney transplantation. Transpl Int. 2015; 28:1162–1171. doi:10.1111/tri.12606
113. Uchida J, Iwai T, Kabei K, et al. Effects of conversion from a twice-daily tacrolimus to a once-daily tacrolimus on glucose metabolism in stable kidney transplant recipients. Transplant Proc. 2014; 46:532–536. doi:10.1016/j.transproceed.2013.11.146
114. Tran D, Vallée M, Collette S, et al. Conversion from twice-daily to once-daily extended-release tacrolimus in renal transplant recipients: 2-year results and review of the literature. Exp Clin Transplant. 2014; 12:323–327. doi:10.6002/ect.2013.0165
115. Moal V, Grimbert P, Beauvais A, et al. A prospective, observational study of conversion from immediate- to prolonged-release tacrolimus in renal transplant recipients in France: The OPALE study. Ann Transplant. 2019; 24:517–526. doi:10.12659/AOT.916043
116. Ho ET, Wong G, Craig JC, et al. Once-daily extended-release versus twice-daily standard-release tacrolimus in kidney transplant recipients: a systematic review. Transplantation. 2013; 95:1120–1128. doi:10.1097/TP.0b013e318284c15b
117. Nankivell BJ, Borrows RJ, Fung CL-S, et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003; 349:2326–2333. doi:10.1056/NEJMoa020009
118. Meier-Kriesche HU, Schold JD, Srinivas TR, et al. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004; 4:378–383. doi:10.1111/j.1600-6143.2004.00332.x
119. Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant. 2011; 11:450–462. doi:10.1111/j.1600-6143.2010.03283.x
120. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003; 349:931–940. doi:10.1056/NEJMoa021744
121. Kaplan B, Schold JD, Meier-Kriesche HU. Long-term graft survival with neoral and tacrolimus: a paired kidney analysis. J Am Soc Nephrol. 2003; 14:2980–2984. doi:10.1097/01.asn.0000095250.92361.d5
122. Nankivell BJ, P’Ng CH, O’Connell PJ, et al. Calcineurin inhibitor nephrotoxicity through the lens of longitudinal histology: comparison of cyclosporine and tacrolimus eras. Transplantation. 2016; 100:1723–1731. doi:10.1097/TP.0000000000001243
123. Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012; 12:1157–1167. doi:10.1111/j.1600-6143.2012.04013.x
124. Gaston RS, Cecka JM, Kasiske BL, et al. Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure. Transplantation. 2010; 90:68–74. doi:10.1097/TP.0b013e3181e065de
125. Hill GS, Nochy D, Bruneval P, et al. Donor-specific antibodies accelerate arteriosclerosis after kidney transplantation. J Am Soc Nephrol. 2011; 22:975–983. doi:10.1681/ASN.2010070777
126. Einecke G, Reeve J, Halloran PF. Hyalinosis lesions in renal transplant biopsies: time-dependent complexity of interpretation. Am J Transplant. 2017; 17:1346–1357. doi:10.1111/ajt.14136
127. Nankivell BJ, Shingde M, Keung KL, et al. The causes, significance and consequences of inflammatory fibrosis in kidney transplantation: the Banff i-IFTA lesion. Am J Transplant. 2018; 18:364–376. doi:10.1111/ajt.14609
128. Schena FP, Pascoe MD, Alberu J, et al.; Sirolimus CONVERT Trial Study Group. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation. 2009; 87:233–242. doi:10.1097/TP.0b013e3181927a41
129. 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; 11:1633–1644. doi:10.1111/j.1600-6143.2011.03573.x
130. Schuler W, Sedrani R, Cottens S, et al. SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation. 1997; 64:36–42. doi:10.1097/00007890-199707150-00008
131. Bertoni E, Larti A, Rosso G, et al. Good outcomes with cyclosporine very low exposure with everolimus high exposure in renal transplant patients. J Nephrol. 2011; 24:613–618. doi:10.5301/JN.2011.6247
132. Budde K, Becker T, Arns W, et al.; ZEUS Study Investigators. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet. 2011; 377:837–847. doi:10.1016/S0140-6736(10)62318-5
133. Cibrik D, Silva HT Jr, Vathsala A, et al. Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation. Transplantation. 2013; 95:933–942. doi:10.1097/TP.0b013e3182848e03
134. Holdaas H, Rostaing L, Serón D, et al.; ASCERTAIN Investigators. Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study. Transplantation. 2011; 92:410–418. doi:10.1097/TP.0b013e318224c12d
135. Mjornstedt L, Sorensen SS, von Zur Muhlen B, et al. Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation. Am J Transplant. 2012; 12:2744–2753. doi:10.1111/j.1600-6143.2012.04162.x
136. Santos SM, Carlos CM, Cabanayan-Casasola CB, et al. Everolimus with reduced-dose cyclosporine versus full-dose cyclosporine and mycophenolate in de novo renal transplant patients: a 2-year single-center experience. Transplant Proc. 2012; 44:154–160. doi:10.1016/j.transproceed.2011.11.055
137. de Fijter JW, Holdaas H, Øyen O, et al.; ELEVATE Study Group. Early conversion from calcineurin inhibitor- to everolimus-based therapy following kidney transplantation: results of the randomized ELEVATE trial. Am J Transplant. 2017; 17:1853–1867. doi:10.1111/ajt.14186
138. Budde K, Zeier M, Witzke O, et al.; HERAKLES Study Group. Everolimus with cyclosporine withdrawal or low-exposure cyclosporine in kidney transplantation from Month 3: a multicentre, randomized trial. Nephrol Dial Transplant. 2017; 32:1060–1070. doi:10.1093/ndt/gfx075
139. Tedesco Silva H Jr, Cibrik D, Johnston T, et al. Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. Am J Transplant. 2010; 10:1401–1413. doi:10.1111/j.1600-6143.2010.03129.x
140. Pascual J, Berger SP, Witzke O, et al.; TRANSFORM Investigators. Everolimus with reduced calcineurin inhibitor exposure in renal transplantation. J Am Soc Nephrol. 2018; 29:1979–1991. doi:10.1681/ASN.2018010009
141. Tedesco-Silva H, Pascual J, Viklicky O, et al.; TRANSFORM Investigators. Safety of everolimus with reduced calcineurin inhibitor exposure in de novo kidney transplants: an analysis from the randomized TRANSFORM study. Transplantation. 2019; 103:1953–1963. doi:10.1097/TP.0000000000002626
142. Vincenti F, Dritselis A, Kirkpatrick P. Belatacept. Nat Rev Drug Discov. 2011; 10:655–656. doi:10.1038/nrd3536
143. Wojciechowski D, Vincenti F. Belatacept in kidney transplantation. Curr Opin Organ Transplant. 2012; 17:640–647. doi:10.1097/MOT.0b013e32835a4c0d
144. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010; 10:535–546. doi:10.1111/j.1600-6143.2009.03005.x
145. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016; 374:333–343. doi:10.1056/NEJMoa1506027
146. Woodle ES, Kaufman DB, Shields AR, et al. Belatacept-based immunosuppression with simultaneous calcineurin inhibitor avoidance and early corticosteroid withdrawal: a prospective, randomized multicenter trial. Am J Transplant. 2020; 20:1039–1055. doi:10.1111/ajt.15688
147. Adams AB, Goldstein J, Garrett C, et al. Belatacept combined with transient calcineurin inhibitor therapy prevents rejection and promotes improved long-term renal allograft function. Am J Transplant. 2017; 17:2922–2936. doi:10.1111/ajt.14353
148. Hricik DE, Formica RN, Nickerson P, et al.; Clinical Trials in Organ Transplantation-09 Consortium. Adverse outcomes of tacrolimus withdrawal in immune-quiescent kidney transplant recipients. J Am Soc Nephrol. 2015; 26:3114–3122. doi:10.1681/ASN.2014121234
149. Ezekian B, Schroder PM, Freischlag K, et al. Contemporary strategies and barriers to transplantation tolerance. Transplantation. 2018; 102:1213–1222. doi:10.1097/TP.0000000000002242
150. Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune tolerance. Cell. 2008; 133:775–787. doi:10.1016/j.cell.2008.05.009
151. Segundo DS, Ruiz JC, Izquierdo M, et al. Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4+CD25+FOXP3+ regulatory T cells in renal transplant recipients. Transplantation. 2006; 82:550–557. doi:10.1097/01.tp.0000229473.95202.50
152. Baan CC, van der Mast BJ, Klepper M, et al. Differential effect of calcineurin inhibitors, anti-CD25 antibodies and rapamycin on the induction of FOXP3 in human T cells. Transplantation. 2005; 80:110–117. doi:10.1097/01.tp.0000164142.98167.4b
153. Whitehouse G, Gray E, Mastoridis S, et al. IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors. Proc Natl Acad Sci U S A. 2017; 114:7083–7088. doi:10.1073/pnas.1620835114
154. Alloway RR, Sadaka B, Trofe-Clark J, et al. A randomized pharmacokinetic study of generic tacrolimus versus reference tacrolimus in kidney transplant recipients. Am J Transplant. 2012; 12:2825–2831. doi:10.1111/j.1600-6143.2012.04174.x
155. Alloway RR, Vinks AA, Fukuda T, et al. Bioequivalence between innovator and generic tacrolimus in liver and kidney transplant recipients: a randomized, crossover clinical trial. Plos Med. 2017; 14:e1002428. doi:10.1371/journal.pmed.1002428
156. Tsipotis E, Gupta NR, Raman G, et al. Bioavailability, efficacy and safety of generic immunosuppressive drugs for kidney transplantation: a systematic review and meta-analysis. Am J Nephrol. 2016; 44:206–218. doi:10.1159/000449020
157. 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. doi:10.1097/TP.0000000000001843
158. van Gelder T; ESOT Advisory Committee on Generic Substitution. European Society for Organ Transplantation Advisory Committee recommendations on generic substitution of immunosuppressive drugs. Transpl Int. 2011; 24:1135–1141. doi:10.1111/j.1432-2277.2011.01378.x
159. Harrison JJ, Schiff JR, Coursol CJ, et al. Generic immunosuppression in solid organ transplantation: a Canadian perspective. Transplantation. 2012; 93:657–665. doi:10.1097/TP.0b013e3182445e9d
160. Alloway RR, Isaacs R, Lake K, et al. Report of the American Society of Transplantation conference on immunosuppressive drugs and the use of generic immunosuppressants. Am J Transplant. 2003; 3:1211–1215. doi:10.1046/j.1600-6143.2003.00212.x
161. European Medicines Agency. Guideline on the investigation of bioequivalence. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf. Accessed January 1, 2020.
162. Health Canada. Guidance Document. Conduct and analysis of comparative bioavailability studies. Available at https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/bioavailability-bioequivalence/conduct-analysis-comparative.html. Accessed January 1, 2020.
163. Food and Drug Administration Guidance for Industry. Bioavailability and bioequivalence studies for orally administered drug products—general considerations. Available at https://www.fda.gov/files/drugs/published/Guidance-for-Industry-Bioavailability-and-Bioequivalence-Studies-for-Orally-Administered-Drug-Products---General-Considerations.PDF. Accessed January 1, 2020.
164. Hulbert AL, Pilch NA, Taber DJ, et al. Generic immunosuppression: deciphering the message our patients are receiving. Ann Pharmacother. 2012; 46:671–677. doi:10.1345/aph.1R028
165. Schwartz JJ, Lee E, Butler AP, et al. The association of tacrolimus formulation switching with trough concentration variability: a retrospective cohort study of tacrolimus use post-kidney transplantation based on national drug code (NDC) numbers. Adv Ther. 2019; 36:1358–1369. doi:10.1007/s12325-019-00950-5
166. Spagnoletti G, Gargiulo A, Salerno MP, et al. Conversion from Prograf to Advagraf in stable kidney transplant recipients: better renal function after 3-year follow-up. Transplant Proc. 2014; 46:2224–2227. doi:10.1016/j.transproceed.2014.08.003
167. Silva HT Jr, Yang HC, Meier-Kriesche HU, et al. Long-term follow-up of a phase III clinical trial comparing tacrolimus extended-release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney transplant recipients. Transplantation. 2014; 97:636–641. doi:10.1097/01.TP.0000437669.93963.8E
168. Rostaing L, Bunnapradist S, Grinyó JM, et al.; Envarsus Study Group. Novel once-daily extended-release tacrolimus versus twice-daily tacrolimus in de novo kidney transplant recipients: two-year results of phase 3, double-blind, randomized trial. Am J Kidney Dis. 2016; 67:648–659. doi:10.1053/j.ajkd.2015.10.024
169. Bunnapradist S, Ciechanowski K, West-Thielke P, et al.; MELT Investigators. Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant. 2013; 13:760–769. doi:10.1111/ajt.12035
170. Tremblay S, Nigro V, Weinberg J, et al. A steady-state head-to-head pharmacokinetic comparison of all FK-506 (tacrolimus) formulations (ASTCOFF): an open-label, prospective, randomized, two-arm, three-period crossover study. Am J Transplant. 2017; 17:432–442. doi:10.1111/ajt.13935
171. Wlodarczyk Z, Squifflet JP, Ostrowski M, et al. Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial. Am J Transplant. 2009; 9:2505–2513. doi:10.1111/j.1600-6143.2009.02794.x
172. de Jonge H, Kuypers DR, Verbeke K, et al. Reduced C0 concentrations and increased dose requirements in renal allograft recipients converted to the novel once-daily tacrolimus formulation. Transplantation. 2010; 90:523–529. doi:10.1097/TP.0b013e3181e9feda
173. Hougardy JM, Broeders N, Kianda M, et al. Conversion from Prograf to Advagraf among kidney transplant recipients results in sustained decrease in tacrolimus exposure. Transplantation. 2011; 91:566–569. doi:10.1097/TP.0b013e3182098ff0
174. Kuypers DR, Peeters PC, Sennesael JJ, et al.; ADMIRAD Study Team. Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Transplantation. 2013; 95:333–340. doi:10.1097/TP.0b013e3182725532
175. Silva HT Jr, Yang HC, Abouljoud M, et al. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant. 2007; 7:595–608. doi:10.1111/j.1600-6143.2007.01661.x
176. Kawai T, Benedict Cosimi A. Induction of tolerance in clinical kidney transplantation. Clin Transplant. 2010; 24(Suppl 22):2–5. doi:10.1111/j.1399-0012.2010.01268.x
177. Leventhal JR, Mathew JM. Outstanding questions in transplantation: tolerance. Am J Transplant. 2020; 20:348–354. doi:10.1111/ajt.15680
178. Stegall MD, Gaston RS, Cosio FG, et al. Through a glass darkly: seeking clarity in preventing late kidney transplant failure. J Am Soc Nephrol. 2015; 26:20–29. doi:10.1681/ASN.2014040378
179. Salvadori M, Bertoni E. Is it time to give up with calcineurin inhibitors in kidney transplantation? World J Transplant. 2013; 3:7–25. doi:10.5500/wjt.v3.i2.7
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.