Tacrolimus in Solid Organ Transplantation: Historical Impact,Current Use,and Future Directions in Immunosuppression

Abstract

Calcineurin inhibitors, particularly tacrolimus, have been a fundamental immunosuppressive treatment in solid organ transplantation for over four decades, helping prevent organ rejection in transplant recipients. Tacrolimus has also proven effective in treating several autoimmune diseases. Despite its effectiveness, the use of tacrolimus has been characterized by challenges related to its narrow therapeutic index—particularly in kidney transplantation—necessitating frequent blood monitoring and dose adjustments. In recent years, improved extended-release formulations have made strides in reducing toxic effects, such as neurotoxicity and nephrotoxicity, and enhancing medication adherence. However, there remains considerable room for improvement, which has the potential to ameliorate long-term graft outcomes and decrease the burden of pill intake, especially for vulnerable patient populations. Recent advances enabling very-extended oral drug delivery present potential opportunities to optimize the peak-trough effects of tacrolimus-based immunosuppression, while also benefitting from the synergy of drug compounding and minimizing pill burden. In this article, we review the history of tacrolimus as a cornerstone of immunosuppression in kidney transplantation, the iterative improvements in outcomes and patient quality-of-life enabled by increasingly extended-release formulations, and the potential outlook for very-extended release formulations in the future.

Keywords

kidney transplant tacrolimus extended-release calcineurin inhibitor immunosuppression

Introduction

Tacrolimus, a calcineurin inhibitor (CNI), has been a dominant force in the field of transplantation medicine since its emergence in the late 1990s. Today, it is the most commonly prescribed CNI for solid organ transplantation, with usage rates over 90%. We will provide a comprehensive analysis of tacrolimus, tracing its history, examining its usage beyond transplantation medicine, and exploring its market impact. We will further review the drug’s various formulations, their respective benefits and shortcomings, and potential avenues for outcomes-focused future developments. The information presented here is critical for understanding the role of tacrolimus in transplantation medicine and its potential impact in treating a host of autoimmune diseases. We will also highlight the need for continued research and development to further improve patient outcomes and quality of life.

Tacrolimus in Transplantation and Beyond

For over 40 years, CNIs have been the cornerstone of immunosuppressive treatment in solid organ transplantation medicine.¹ Originally, cyclosporine was the CNI of choice for transplant recipients. First used in kidney transplantation in 1978 by Calne and colleagues,^2,3 later studies including a randomized single-center study by Hakala et al and two large multicenter trials demonstrated dramatic improvements in 1-year acute rejection rates and kidney allograft survival rates in cyclosporine and corticosteroid-based regimens over those that utilized azathioprine and corticosteroids.^4-6 Subsequent research in heart, lung, and liver transplantation solidified cyclosporine’s superiority, and by the late 1990s cyclosporine was the backbone of maintenance immunosuppression in solid organ transplantation.⁷ However, it was around this same time that tacrolimus, a new CNI, emerged as a compelling alternative to cyclosporine. Initial research in liver transplantation by Starzl and Fung at the University of Pittsburg demonstrated reduced rates of rejection in patients treated with tacrolimus as compared to those treated with cyclosporine.⁸ These studies were further supported by a large randomized controlled trial of kidney transplant recipients by Pirsch et al. in 1997 that showed a 15% lower acute rejection rate in tacrolimus-treated patients as compared to cyclosporine-treated patients, but with similar graft survival rates.⁹ Eventually, the use of tacrolimus became widespread in thoracic organ transplantation as well, as studies in heart and lung patients also demonstrated decreased rates of acute rejection and excellent graft survival rates.⁷ By 1999 more than 30% of US kidney transplant programs used tacrolimus-based regimens.⁷ By 2001, tacrolimus overtook cyclosporine as the main CNI prescribed for solid organ transplantation and in 2009 around 90% of all solid organ transplant recipients used tacrolimus (Figure 1).^7,10 In the past decade, tacrolimus has continued to dominate as the CNI of choice in solid organ transplantation and has led to excellent allograft and patient outcomes.¹¹ Nowhere is this more true than in kidney transplantation; 1-year deceased and living donor allograft survival rates are upwards of 94%, 1-year rejection rates are less than 10%, and 1-year patient survival rates are approximately 95%.¹² The widespread adoption of tacrolimus as the standard-of-care for transplant immunosuppressive regimens has also led to a formal endorsement of tacrolimus by important transplant consensus groups such as Kidney Disease Improving Global Outcomes (KDIGO).¹³

Figure 1.

Initial maintenance immunosuppression used for kidney transplant recipients by year, 1995-2018. Since being approved by the US Food and Drug Administration in 1994, tacrolimus usage steadily has become the calcineurin inhibitor of choice, surpassing cyclosporine by 2001 and approaching usage rates around 90% for maintenance immunosuppression by 2009. Data from Pilch et al, 2022, OPTN Annual Data Report 2011, and OPTN Annual Data Report 2018

As the use of tacrolimus in transplant medicine has developed, other subspecialties have also looked to the drug as either first-line or second-line treatment for a host of autoimmune diseases requiring immunosuppression. Tacrolimus is approved by the United States Food and Drug Administration (FDA) as first-line prophylaxis for rejection in solid organ transplantation when used in combination with other immunosuppressants, but it is also used off-label for a myriad of kidney glomerulopathies (such as primary focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease), systemic lupus erythematosus (SLE), psoriasis, rheumatoid arthritis, Crohn’s disease, refractory ulcerative colitis, myasthenia gravis, endogenous uveitis, Sjogren’s syndrome, and dermatologic conditions such as severe dermatitis and severe eczema.¹⁴ The widespread usage of this drug in other disease states is largely due to its potent T-cell immunosuppressive effects and relatively well tolerated medication profile.

Tacrolimus by The Numbers

The successful allograft and patient outcomes associated with tacrolimus and current standard-of-care immunosuppression regimens has had a significant impact on the growth of modern transplantation. In 2022 alone, there were 157,494 solid organ transplants performed across 91 different countries globally, with 43,743 of those transplants performed in the United States (Figure 2).¹⁵ The overwhelming majority of these patients are on tacrolimus for maintenance immunosuppression. With over 100,000 individuals awaiting a transplant on the US national transplant waitlist and transplantation rates expected to increase in the next 5 years worldwide, the number of future patients who will be dependent on tacrolimus as part of their maintenance regimen is guaranteed to increase. Furthermore, the use of tacrolimus for a vast array of off-label indications creates other potential patient populations that may benefit from this medication. There are, for example, approximately 5 million inflammatory bowel disease (IBD) patients worldwide, with approximately 3 million IBD patients in the US,¹⁶ and approximately 120,000 cases of kidney specific glomerulopathy worldwide.

Figure 2.

Global transplants in 2022 by organ type. Transplants for all organ types totaled 157,324 and kidney transplants totaled 102,090 globally. Data from the Global Observatory on Donation and Transplant 2022 report (published October 2023, https://www.transplant-observatory.org/)

Given how well patients do on tacrolimus-based regimens, the space for new drug development for maintenance immunosuppression in transplantation is small and future continued dependence on tacrolimus in the field is likely. The FDA has historically looked at short-term, 1-year outcomes for patient and allograft survival as valid endpoints for transplant studies. With tacrolimus-based regimens having patient and allograft survival rates upwards of 95% and 94% respectively, it would be difficult for any putative novel agent to demonstrate further improvement. Moreover, this lowers the incentive for new drug development, as it is unlikely that any new drug will show true superiority over current tacrolimus-based regimens. This relative lack of competition has further solidified tacrolimus as the likely perpetual CNI of choice in transplantation medicine for the foreseeable future.

Mechanism of Action and Current Formulations

Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis.¹⁷ It exerts its immunosuppressive effects by inhibiting T lymphocyte activation and proliferation as well as the T-helper-cell-dependent B cell response.¹⁸ It works by binding to FK506-binding protein 12 intracellularly within the T lymphocyte and forming a complex to inhibit phosphatase activity of calcineurin (Figure 3). This leads to inhibition of downstream signaling and subsequent production of several cytokines, including interleukin-2 (IL-2), which is necessary for T-cell response.¹⁴

Figure 3.

Tacrolimus mechanism of action. Tacrolimus binds FK506 binding protein 12 intracellularly to inhibit calcineurin. Calcineurin inhibition in turn reduces NFAT-mediated transcription, leading to decreased cytokine production, in particular of interleukin-2. Created in BioRender. (2025) https://BioRender.com/dwalyca

In addition to intravenous formulations and granules for oral solution, tacrolimus is available in three different oral formulations with varying pharmaceutical properties and pharmacokinetic profiles, including an immediate release capsule (Prograf^®, Astellas Pharma, Northbrook, IL; [IR-Tac]), an extended release capsule (Astagraf XL^®, Astellas Pharma, Northbrook, IL; [ER-Tac]), and an extended release tablet (Envarsus XR^®, Veloxis Pharmaceuticals, Edison, NJ; [LCPT]).^14,19,20 As these oral formulations are the ones near-universally used by transplant recipients on maintenance therapy, our review will focus on these formulations.

Tacrolimus Immediate Release (IR-Tac)

IR-Tac (Prograf^®) was approved by the FDA in 1994 and has since been the mainstay of immunosuppressive therapy for solid organ transplantation.¹⁴ It is approved for the prophylaxis of organ rejection patients receiving allogeneic liver, kidney, or heart transplants, when used in combination with other immunosuppressants. It is an immediate release capsule available in 0.5 mg, 1 mg, and 5 mg strengths and requires twice daily dosing in adults to achieve consistent therapeutic blood concentrations.¹⁴

Tacrolimus Extended Release Capsules (ER-Tac)

ER-Tac (Astagraf XL^®) was FDA approved in 2013 for the prophylaxis of organ rejection in kidney transplant recipients in combination with other immunosuppressants and is available in 0.5 mg, 1 mg, and 5 mg capsules.¹⁹ The extended release formulation utilizes the inactive ingredient ethylcellulose to control water permeation in the GI tract, allowing for prolonged drug release over approximately 24 hours, and subsequent once daily dosing.¹⁹

Tacrolimus Extended Release Tablets (LCPT)

LCPT (Envarsus XR^®) was FDA approved in 2015 and is indicated for prophylaxis of organ rejection in de novo kidney transplant patients and in kidney transplant patients converted from tacrolimus immediate-release formulations, when used in combination with other immunosuppressants.²⁰ It is available in 0.75 mg, 1 mg, and 4 mg tablets and has a unique formulation that uses MeltDose^® technology in which tacrolimus is reduced to a molecular level and applied to an inert carrier matrix, which is then pressed into a tablet. Due to the carrier matrix, the drug is slowly released throughout the gastrointestinal tract after oral administration, allowing for once daily administration.²¹

Comparison of Formulations

All three formulations of tacrolimus were compared in an open-label, prospective, randomized, head-to-head pharmacokinetic study by Tremblay et al., in which the novel formulation of LCPT demonstrated pharmacokinetic advantages including improved bioavailability, lower dosing requirements, and a smoother pharmacokinetic curve with fewer fluctuations.²² These findings were consistent with prior studies comparing LCPT to IR-Tac. The pharmacokinetic profile of ER-Tac was similar to that of IR-Tac, however, despite only being dosed once daily.

The average peak concentration (C_max) values for LCPT, ER-Tac, and IR-Tac were 13.9 ± 5.3 ng/mL, 13.2 ± 4.4 ng/mL, and 14.5 ± 5.5 ng/mL, respectively, and the average minimum concentration (C_min) values were 6.8 ± 2.9 ng/mL, 5.1 ± 1.8 ng/mL, and 6.1 ± 1.7 ng/mL.²² When exposure was normalized to observed exposure of IR-Tac, the C_max was approximately 17% lower for LCPT than for IR-Tac or ER-Tac. The time to maximum concentration (T_max) was significantly longer in the LCPT group at 5.9 hours vs 1.9 hours in the ER-Tac group and 1.5 hours in the IR-Tac group (P < 0.001), and the 24-hour area under the curve (AUC_0-24) was also significantly greater in the LCPT group at 213.4 ± 83.1 h*ng/mL vs 165 ± 50 h*ng/mL in the ER-Tac group and 176.5 ± 50.8 h*ng/mL in the IR-Tac group. The intraday peak-to-trough fluctuation was significantly lower for LCPT compared with IR-Tac and ER-Tac. A depiction of the observed mean whole blood time-concentration curves and the normalized to IR-Tac mean whole blood time-concentration curves are reproduced in Figure 4.²²

Figure 4.

Whole blood concentrations of tacrolimus with IR-Tac, ER-Tac, and LCPT. IR-Tac concentrations are shown in green, ER-Tac in yellow, and LCPT in blue. (A) shows curves using a conversion factor of 1:1:0.80 for IR-Tac to ER-Tac to LCPT while B) shows curves using a conversion factor of 1:1.08:0.70 for IR-Tac to ER-Tac to LCPT. LPTC has a considerably longer time-to-peak, lower maximum concentration, and higher minimum concentration using either conversion factor. Reprinted with permission from the original article in the American Journal of Transplantation, Volume 17, S. Tremblay 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,” Pages 432-442, Copyright American Society of Transplant Surgeons (2017)

Based on the results of this study, the authors concluded that a 36% total daily dose reduction is recommended when converting from ER-Tac to LCPT and a 30% total daily dose reduction when converting from IR-Tac to LCPT whereas an 8% increase in total daily dose could be considered when converting from IR-Tac to ER-Tac.²²

Benefits

Since its introduction into the world of transplantation by Starzl and Fung in the late 1990s, tacrolimus’s superiority over cyclosporine has been consistently demonstrated by numerous studies looking at both short and long-term outcomes in transplant patients.^1,7 Initial studies were published by Starzl and Fung while at the University of Pittsburgh in the area of liver transplantation.⁸ The team looked at 154 low risk liver transplant recipients and randomized them to either a tacrolimus treatment group or a cyclosporine treatment group. They found that the 1-year patient and allograft survival rates were 92% and 88%, respectively, for tacrolimus-treated recipients, compared with 85% and 79%, respectively, for cyclosporine-treated recipients.⁸ A follow-up study at two years revealed that the increase in patient and allograft survival in the tacrolimus treatment arm was retained. In both studies, rejection was statistically lower in the tacrolimus treated group as compared with the cyclosporine treated group.⁸

The application of tacrolimus to kidney transplantation was an extension of the experiences gained in liver transplantation. As previously mentioned, one of the earliest clinical trials comparing tacrolimus and cyclosporine was a 1997 multicenter randomized trial by Pirsch et al.⁹ This study found a significantly lower incidence of acute rejection at one year in the tacrolimus group (30.7% vs 46.4%; P < 0.001) and a significantly lower incidence of moderate-to-severe rejection (10.8% vs 26.5%; P < 0.001).⁹ At five years, the rate of patients with serum creatinine levels greater than 150 μg/L was lower in the tacrolimus group (40.4% vs 62%; P < 0.001).⁹ Finally, there were no differences in the 1-year patient survival (95.6% vs 96.6%; P < 0.001) and graft survival (91.2% vs 87.9%; P < 0.001) rates between the two groups.⁹ Webster and colleagues, 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) and less acute rejection (RR = 0.69).²³ Ekberg et al. randomized kidney transplant recipients to receive either standard dose cyclosporine, low-dose cyclosporine, low-dose sirolimus, or low-dose tacrolimus in combination with mycophenolate (MMF) and corticosteroids.²⁴ The study showed that at 1-year post transplant, the low-dose tacrolimus arm had lower rates of acute rejection and higher graft survival compared with the other three groups.²⁴ At 3-year post-transplant, the low-dose tacrolimus arm continued to have the lowest rates of acute rejection and the highest graft survival.²⁴

In addition to better short and long-term allograft outcomes seen in tacrolimus over cyclosporine, several trials have confirmed better overall renal function associated with tacrolimus compared with cyclosporine. Ekberg et al. showed that kidney function as determined by the mean calculated glomerular filtration rate (GFR) was higher in patients receiving low-dose tacrolimus (65.4 mL/minute) than in the other three groups (range, 56.7 to 59.4 mL/minute).²⁴ Jurewicz et al. likewise showed that GFR was significantly better in tacrolimus-treated patients from three months post-transplant.²⁵ Moreover, they showed that normal kidney function was maintained throughout 5-year follow-up in a significantly higher proportion of non-rejecting patients treated with tacrolimus than with cyclosporine microemulsion (58% vs 10%, respectively at five years; P = 0.002).²⁵ This preservation of GFR seen in tacrolimus-based regimens as compared to cyclosporine-based regimens is attributed to an inherently lesser nephrotoxicity in tacrolimus as compared to cyclosporine.

Finally, several studies have demonstrated that tacrolimus has a more favorable tolerability profile than cyclosporine. One major benefit in this regard is that tacrolimus has been demonstrated to have a better lipid profile, and therefore lesser cardiovascular side effects, as compared to cyclosporine.^26,27 Starzl and Fung demonstrated a lower incidence of hypertension in tacrolimus-treated patients as compared to cyclosporine-treated patients in their University of Pittsburg experience.⁸ Margreiter et al. conducted a multicenter study converting kidney transplant recipients on cyclosporine to tacrolimus therapy and successful outcomes were achieved in resolving hyperlipidemia and hypertension.²⁸ That same study showed improvement in cosmetic side effects such as gingival hyperplasia and hypertrichosis in patients converted from cyclosporine therapy to tacrolimus therapy.²⁸ Webster and colleagues’ study also demonstrated fewer cosmetic side effects in tacrolimus-treated patients vs cyclosporine-treated patients.²³

Shortcomings

Although it is well established that tacrolimus is the preferred CNI due to improved efficacy and a more favorable tolerability profile, there are still some key limitations associated with the drug that warrant further discussion. These shortcomings can be broadly divided into adverse side effects due to tacrolimus’ mechanism of action and adverse side effects more dependent on tacrolimus’ narrow therapeutic index and associated toxicities.

Side Effects due to Mechanism of Action

New onset diabetes after transplantation (NODAT) is a common complication occurring in 2-53% of all solid organ transplant recipients.²⁹ In addition to standard risk factors for developing diabetes, CNIs are also known to increase the risk of developing diabetes post-transplant due to their mechanism of action within the pancreatic cells.^29,30 CNIs cause toxicity to pancreatic beta islet cells by inhibiting NFAT signaling and thereby, decreasing insulin production.³¹ Although NODAT is a risk associated with both tacrolimus and cyclosporine, the incidence is higher with tacrolimus.^30,32 In an open-label, randomized, multicenter study comparing the incidence of NODAT or impaired fasting glucose six months after kidney transplantation in over 600 patients, 33.6% in the tacrolimus treatment group developed NODAT or impaired fasting glucose vs 26% of patients in the cyclosporine treatment group (P = 0.046).³²

Electrolyte disturbances are another common side effect related to the mechanism of action of CNIs. Hyperkalemia is one of the most common electrolyte abnormalities seen with CNIs and is more prevalent with tacrolimus than cyclosporine.³³ The mechanism by which CNIs cause hyperkalemia is multifactorial and there are several proposed mechanisms including suppression of the renin-angiotensin-aldosterone system, distal renal tubular acidosis, increased aldosterone resistance due to downregulation of mineralocorticoid receptors, and inhibitory effects on Na+-K+-ATPase in collecting ducts.^30,34 Hyperkalemia can cause serious cardiac manifestations including electrocardiogram changes, arrhythmias, and cardiac arrest, and therefore, levels are routinely monitored in transplant recipients and appropriately treated.³⁵ Hypomagnesemia is another common electrolyte disturbance seen with the use of CNIs, and is caused by downregulation of magnesium transport proteins in the distal tubules leading to magnesium wasting.³⁵ Although most patients with low magnesium levels remain asymptomatic, serious neuromuscular and cardiovascular complications can occur and hypomagnesemia is also linked to insulin resistance.³⁵ Therefore, magnesium is also routinely monitored and treatment with magnesium supplementation is performed if indicated.

Side Effects due to Narrow Therapeutic Index

Tacrolimus has a narrow therapeutic index requiring frequent monitoring of blood trough concentrations and dose titrations to achieve goal trough levels. Goal trough levels vary depending on the organ transplanted, time from transplantation, immunologic risk, and tolerability, but generally target trough levels range from 5-20 ng/mL with subtherapeutic levels associated with an increased risk of allograft rejection and supratherapeutic levels associated with an increased risk of toxicities.^36,37 There is large inter- and intra-patient variability with oral CNIs due to their pharmacokinetic profile, which necessitates individualized patient dosing.

Tacrolimus has poor and widely variable oral absorption with approximately 20% bioavailability.³⁸ The time to peak is approximately 0.6 to 6 hours following oral administration of IR tacrolimus and C_max ranges from 19 ± 10.3 ng/mL to 68.5 ± 30 ng/mL.⁸ Absorption is significantly impacted by coadministration with food, which decreases both the rate and extent of absorption. When given with high-fat meals, the time to peak is prolonged, the C_max is decreased by 25-77%, and the area under the curve (AUC) is decreased by 25-37%.¹⁴ Although it is recommended to administer tacrolimus on an empty stomach for optimal absorption, this is typically not practical for transplant patients since multiple medications are taken at the same time, and food helps improve gastrointestinal tolerability. It is therefore more common in practice, however, to simply advise patients to be consistent with taking tacrolimus either with or without food.³⁹ Absorption of tacrolimus occurs throughout the gastrointestinal tract after oral administration, and bioavailability is also affected by pre-systemic metabolism in the intestinal wall via CYP3A4 enzymes and P-glycoprotein, making tacrolimus highly susceptible to drug and food interactions.⁴⁰ Furthermore, tacrolimus pharmacokinetics exhibit diurnal variations with decreased and delayed absorption and slower elimination after the evening dose.⁴¹

Tacrolimus is extensively metabolized by the cytochrome P450 system in the liver and gut and undergoes significant first-pass metabolism.¹⁴ Because of this, drug-drug interactions are of particular concern as CYP3A4 inhibitors significantly decrease the metabolism of tacrolimus causing increased blood levels, whereas CYP3A4 inducers increase the metabolism and reduce blood levels.⁴⁰ Concomitant administration of medications that affect the CYP3A4 system requires increased therapeutic drug monitoring to guide dose adjustments and to ensure appropriate tacrolimus concentrations are maintained. Another important consideration is genetic polymorphisms that contribute to interpatient variability in tacrolimus pharmacokinetics. CYP3A5 is a dominant enzyme responsible for the metabolism of tacrolimus. CYP3A5*1 is a functional allele while *3, *6, and *7 are non-functional alleles.⁴² Carriers of homozygous CYP3A5*1/*1 alleles are considered to be rapid metabolizers and carriers of only one functional allele are classified as intermediate metabolizers. CYP3A5 nonexpressers or individuals carrying two nonfunctioning alleles are poor metabolizers.^42,43 Rapid metabolizers require 1.5-2 times higher doses of tacrolimus than nonexpressers to achieve therapeutic trough levels and are at a higher risk of rejection due to subtherapeutic levels, non-adherence due to increased dose requirements, and peak-related toxicities.⁴⁴ The majority of White patients (80-85%) are poor metabolizers while approximately 50% of Black patients express the *1 allele and are rapid metabolizers.⁴⁵ Therefore, Black patients often require higher tacrolimus doses to achieve therapeutic trough levels and are at a higher risk of rejection due to subtherapeutic levels.^45,46

Another factor that must be considered when dosing tacrolimus is recipient age. Pediatric patients typically require significantly higher dosages than adult patients to achieve therapeutic trough levels due to differences in the developing cytochrome P450 system.⁴⁷ Conversely, elderly patients typically require lower dosages.⁴⁸ Although pharmacokinetic studies are lacking in elderly transplant recipients, it has been demonstrated that elderly patients have a lower risk of rejection and a higher risk of experiencing adverse effects from immunosuppression.⁴⁸ Therefore, reduced immunosuppression is recommended in this patient population and has been associated with improved graft survival.⁴⁸

Neurotoxicity is a dose-related adverse effect of CNIs that is more common with tacrolimus than cyclosporine.⁴⁹ Presentation can range from mild effects such as headaches, tremors, insomnia, vertigo, and/or paresthesia to more severe, but rare, complications including seizures, delirium, hallucinations, blindness, akinetic mutism, and encephalopathy.⁴⁹ While the exact mechanism of CNI-induced neurotoxicity is not known, it’s thought that tacrolimus may increase the permeability of the blood brain barrier and—once within the central nervous system—may cause neurotoxic effects through calcineurin inhibition.⁵⁰ More importantly, it appears that the risk for neurotoxicity is associated with higher peak drug levels, and therefore considerations should be made to decrease peak levels by reducing the dose of tacrolimus while still maintaining effectiveness, or potentially by using an extended-release formulation of tacrolimus with a smoother pharmacokinetic curve.^49,51,52

In the STRATO study, an open-label, multicenter, prospective phase 3b study, Langone and colleagues evaluated the efficacy and safety of switching from IR-tac to extended release LCPT in kidney transplant recipients experiencing clinically significant tremors on a stable dose of tacrolimus.⁵² Tremor was assessed at baseline and again 7 days after conversion from IR-tac to LCPT by independent, blinded movement disorder neurologists utilizing a validated tremor rating scale to measure the severity of the tremor, as well as quality of life questionnaires and patient and physician qualitative assessments. Upon conversion from a stable dose of IR-tac, the total daily dose of LCPT was reduced by 30% in non-Black patients and by 15% in Black patients with goal trough levels maintained between 3 and 12 ng/mL.⁵² After conversion, the mean absolute change in total tremor score demonstrated significant improvement on day 14 (P < 0.0001).

Nephrotoxicity may also be a side effect related to higher drug levels in patients treated with CNIs. Although the risk appears to be greater with cyclosporine, tacrolimus is known to cause to both acute and chronic nephrotoxicity.²⁴ Acute nephrotoxicity is dose-dependent and reversible upon dose reduction.⁵³ It is caused by vasoconstriction of the afferent arterioles and increased vascular resistance due to an increase in endothelin and thromboxane and activation of the renin-angiotensin-aldosterone system (RAAS) as well as a reduction of vasodilation factors, including prostacyclin, prostaglandin E₂, and nitric oxide, which leads to reduced blood flow.³⁴ Acute nephrotoxicity is typically associated with tacrolimus trough blood levels greater than 20 ng/mL, but can be seen at any level.³⁰ Unlike acute CNI nephrotoxicity, chronic CNI nephrotoxicity is not reversible and leads to a gradual decline in kidney function. CNI exposure over time has been shown to cause irreversible kidney damage including arteriolar hyalinosis, interstitial fibrosis, tubular atrophy, and glomerulosclerosis.³⁴

Risk for Non-Adherence

Medication non-adherence after transplantation occurs frequently in solid organ transplant recipients, with reported rates as high as 20-37%.⁵⁴ Non-adherence is a major cause of rejection and graft loss and has significant economic implications as well. Therefore, understanding medication adherence and strategies to overcome barriers to adherence is of utmost importance. There are several known general risk factors for non-adherence including financial barriers, low socioeconomic status, young age, and poor health literacy.⁵⁵ Transplant recipients experience additional barriers related to the complexity of their disease state and post-transplant treatment regimen, including frequent follow up visits, lifelong medication requirements, a large pill burden, unfavorable side effects, and frequent medication dosing and dose changes.⁵⁵ IR-Tac is the most commonly used formulation post-transplant and requires twice daily dosing with consistent timing, frequent therapeutic drug monitoring due to its narrow therapeutic index, and subsequent (and sometimes frequent) dose changes to ensure therapeutic levels.⁵⁶ Furthermore, because of the strengths available and the necessity for dose titration, patients are often required to take several capsules at each dosing time to achieve the proper dose. This exacerbates the already large pill burden in transplant recipients as well as the complexity of the medication regimen, which can contribute to non-adherence.

Most strategies to improve adherence are largely patient-focused, targeting educational, behavioral, and technological interventions.⁵⁴ However, since the advent of once-daily tacrolimus formulations, several studies have showed promising effects on adherence.^56-59 In a large randomized controlled trial, the ADMIRAD Study Team evaluated adherence in over 200 kidney transplant patients who were randomized to either continuing twice daily IR tacrolimus or to convert to an extended-release once-daily formulation of tacrolimus.⁵⁷ They found that patients in the once-daily group demonstrated significantly improved adherence compared to patients in the twice-daily group (88.2% vs 78.8%; P = 0.0009).⁵⁷ Similar findings were reported by a Canadian group that evaluated medication adherence in 46 stable kidney transplant recipients who were randomized to either twice-daily or once-daily tacrolimus, with the once-daily group demonstrating significantly improved adherence.⁵⁶ Improved medication adherence when decreasing the pill burden by converting from twice daily to once daily tacrolimus has been seen across other organ groups as well, including liver, heart, and lung transplant recipients.^60-62

Discussion: What is Next for Tacrolimus?

While tacrolimus has become the gold standard in transplant immunosuppression, ongoing challenges remain that continue to drive interest in optimizing its formulation. Neurotoxicity and nephrotoxicity, for example, remain important dose-related complications, particularly associated with high peak serum levels. At the same time, low trough levels are associated with a heightened risk of allograft rejection. Balancing these competing pharmacologic risks is made even more difficult by the drug’s narrow therapeutic index, significant inter- and intra-patient variability, and the impact of food, drug-drug interactions, and genetic polymorphisms on bioavailability (Figure 5).

Figure 5.

Summary of the issues associated with elevated and low serum tacrolimus levels in kidney transplant recipients. Elevated peak serum tacrolimus levels are associated with neurotoxicity and nephrotoxicity, new-onset diabetes after transplant (NODAT), and electrolyte disturbances, amongst other issues. Low serum tacrolimus levels increase the risk of acute rejection episodes and allograft loss. Created in BioRender. (2025) https://BioRender.com/j41h14g

Extended-release (ER) formulations have improved the pharmacokinetic profile of tacrolimus, reducing peak-to-trough variability and facilitating once-daily dosing. These developments have led to enhanced tolerability, improved patient satisfaction, and better adherence. However, even these once-daily formulations may not fully address the underlying issues that contribute to toxicity, variability, and non-adherence in some patient populations. The future of tacrolimus therapy may lie in the development of very extended-release (VER) formulations designed to provide more stable drug exposure over longer periods—ranging from several days to potentially a full week or longer.

Recent advances in oral drug delivery technology—such as gastroretentive systems, controlled-release polymers, and novel depot-based drug carriers—offer exciting opportunities to rethink how tacrolimus is delivered. For example, gastroretentive delivery systems that prolong the residence time of a formulation in the stomach or proximal intestine could theoretically allow for a VER formulation of tacrolimus that achieves stable blood concentrations with minimal day-to-day fluctuation.^63,64 These innovations could help smooth the pharmacokinetic curve even further, reducing peak-associated adverse effects (such as tremors, headaches, and nephrotoxicity) while maintaining trough levels sufficient to prevent rejection. Importantly, a VER formulation could also lessen the impact of factors that currently necessitate frequent dose adjustments, such as diurnal variation in absorption or genetic differences in CYP3A5 metabolism.

One of the most important potential benefits of a VER tacrolimus formulation would be enhanced medication adherence. As has been well-documented, adherence rates among transplant recipients remain suboptimal, with up to 20-37% of patients demonstrating some form of non-adherence. This is particularly true in vulnerable populations such as adolescents, patients with mental health conditions, and those from socioeconomically disadvantaged backgrounds.⁶⁵ With twice-daily dosing regimens requiring meticulous timing, multiple capsules per dose, and regular therapeutic drug monitoring, the pill burden and complexity of treatment can be overwhelming. While once-daily dosing with current extended-release formulations has already improved adherence in some patient populations, further reductions in dosing frequency and improved tolerability could have a substantial additional impact.^60-62

Moreover, VER formulations of tacrolimus may allow for a more patient-centric approach to immunosuppression. For example, a formulation that supports multi-day dosing could create a valuable buffer in cases of delayed or missed doses, reducing the risk of underexposure and subsequent rejection. This would be particularly useful for patients with irregular schedules, cognitive impairment, or barriers to frequent medication administration. For adolescent patients transitioning from pediatric to adult care—a population that is especially susceptible to non-adherence—reduced dosing frequency could be a key component in improving long-term outcomes.

Certain populations may also derive unique clinical benefits from VER formulations. Rapid metabolizers, due to genetic or non-genetic factors, often require higher tacrolimus doses to reach therapeutic levels. These individuals are at increased risk of both underexposure and adverse effects, particularly if the formulation they are taking results in fluctuating blood levels. Evidence suggests that extended-release tacrolimus formulations already mitigate some of this variability, and a VER formulation could further smooth the pharmacokinetic profile, potentially improving drug exposure consistency regardless of genotype.⁶⁶

Additionally, patients at high risk for tacrolimus-related toxicity, such as those with pre-existing neurological conditions, cardiovascular comorbidities, or reduced renal reserve, may benefit from a formulation that lowers peak concentrations and maintains stable levels over time. In this respect, a VER tacrolimus could help prevent adverse outcomes by minimizing acute toxicity while still achieving effective immunosuppression.

While the clinical and pharmacokinetic rationale for a VER tacrolimus formulation is compelling, significant research and development is still needed to bring such a product to market. Studies would be required to evaluate not only the safety and efficacy of these formulations, but also their pharmacoeconomic impact. Given the high cost of managing graft rejection and the long-term consequences of non-adherence or toxicity, it is likely that investment in VER formulations would be cost-effective over time. Data on extended-release tacrolimus suggest that improved outcomes and reduced healthcare utilization may offset the development and production costs of such therapies.

In summary, tacrolimus has transformed the landscape of transplant medicine and will likely remain foundational to immunosuppressive regimens for the foreseeable future. However, evolving patient needs and a better understanding of pharmacokinetic variability highlight opportunities to further optimize its delivery. Very extended-release formulations represent a promising potential next step in the evolution of tacrolimus therapy. With the potential to reduce toxicity, improve adherence, and expand the therapeutic window, these innovations could have a meaningful and lasting impact on transplant outcomes and patient quality of life.

Conclusion

Tacrolimus is the mainstay of maintenance immunosuppression in solid organ transplantation. Due to its effectiveness, with excellent, near-maximal short-term outcomes, tacrolimus is unlikely to be dethroned in the foreseeable future. Patients have been well-served by increasingly extended formulations of tacrolimus, which have leveraged favorable pharmacokinetic profiles to flatten the curve of serum tacrolimus levels. This has had the benefit of reducing toxic effects (namely nephrotoxicity and neurotoxicity) and improving graft outcomes. However, there is considerable room for improvement, as well as for increasing medication adherence and reducing pill burden. Future development of tacrolimus formulations with optimized and extended pharmacokinetic properties could significantly improve patient outcomes and quality-of-life.

Footnotes

Acknowledgements

We wish to thank our team at the NYU Langone Transplant Institute and especially our entire team of transplant pharmacists for their valuable insights and feedback on this topic.

ORCID iD

Ian S. Jaffe

Author Contributions

R. Dieter, I.S. Jaffe, and A. Mattoo: Conception, Analysis, Interpretation, Writing – Original Draft, Writing – Editing, Critical Review.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: I.S. Jaffe was supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR001445. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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