Drugs

, Volume 46, Issue 4, pp 746–794 | Cite as

Tacrolimus

A Review of its Pharmacology, and Therapeutic Potential in Hepatic and Renal Transplantation
  • David H. Peters
  • Andrew Fitton
  • Greg L. Plosker
  • Diana Faulds
Drug Evaluation

Abstract

Synopsis

Tacrolimus (FK 506) is a macrolide immunosuppressant which possesses similar but more potent immunosuppressant properties compared with cyclosporin, inhibiting cell-mediated and humoral immune responses. Like cyclosporin, tacrolimus demonstrates considerable interindividual variation in its pharmacokinetic profile. This has caused difficulty in defining the optimum dosage regimen and has highlighted the usefulness of therapeutic drug monitoring. Most clinical studies with tacrolimus have neither been published in their entirety nor subjected to extensive peer review; there is also a paucity of published randomised investigations of tacrolimus versus cyclosporin, particularly in renal transplantation. Despite these drawbacks, tacrolimus has shown notable efficacy as a rescue or primary immunosuppressant therapy when combined with corticosteroids in adult and paediatric recipients following liver or kidney transplantation. Indeed, graft salvage rates in patients experiencing rejection or drug-related toxicity were ⩾50%, although data in renal transplantation are limited. Compared with cyclosporin as a primary immunosuppressant, tacrolimus showed comparable or greater patient/graft survival rates in liver allograft recipients (where cost savings associated with reduced hospitalisation costs were evident in one study), and comparable patient/graft survival in patients following kidney transplantation. Worthy of note was the efficacy of tacrolimus as a primary immunosuppressant in patients who received en bloc kidney allografts. The incidence of rejection was largely reduced following rescue therapy with tacrolimus and was generally lower (notably for refractory rejection) than that observed for cyclosporin, at least in liver allograft recipients. This was reflected in less need for adjunct immunotherapy including antilymphocyte preparations for the treatment of rejection episodes. The potential for reduction or withdrawal of corticosteroid therapy with tacrolimus appears to be a distinct advantage compared with cyclosporin, and this may be enhanced by the reduced incidence of infectious complications and of hypertension and hypercholesterolaemia reported by some investigators. In other respects, however, the tolerability profile of tacrolimus appears to be broadly similar to that of cyclosporin.

Against this background, preliminary data indicate that tacrolimus provides a valuable therapeutic alternative to retransplantation in patients experiencing liver or kidney graft rejection or drug-related toxicity. Pending confirmation of initial randomised studies and preliminary results from large randomised investigations, tacrolimus may well be considered as an alternative primary immunosuppressant to cyclosporin in hepatic (particularly) and renal transplantation. Furthermore, the steroid-sparing effects of tacrolimus, although of benefit to all patient groups, may prove to be of particular worth in children and in en bloc kidney recipients. In these patients tacrolimus may well emerge as the drug of choice.

Clearly, further experience in the clinical setting will help clarify the role of tacrolimus in transplantation surgery. Nevertheless, this new immunosuppressant has already demonstrated its usefulness as an addition to the limited immunotherapeutic options available to date.

Pharmacodynamic Properties

The macrolide immunosuppressant, tacrolimus, displays similar, but more potent, immunosuppressive properties to cyclosporin, inhibiting cell-mediated and humoral immune responses. Through its interaction with a specific cytoplasmic immunophilin, tacrolimus inhibits calcium-dependent signal transduction pathways in T cells, thereby preventing transcription of a discrete set of lymphokine genes. In vitro, tacrolimus is 10 to 100 times more potent than cyclosporin in inhibiting allogen- and mitogen-induced stimulation of T cell proliferation and the production of interleukin (IL)-2 and other growth-promoting cytokines (IL-3, IL-4, interferon-γ, tumour necrosis factor-α and granulocyte-macrophage colony-stimulating factor), the mixed lymphocyte response, generation of cytotoxic T cells, and B cell activation. Tacrolimus does not, however, inhibit the secondary proliferation of activated T cells in response to IL-2. In vivo, tacrolimus is approximately 10 times more potent than cyclosporin in suppressing T cell-dependent antibody production, graft-versus-host reactivity and delayed type hypersensitivity. Tacrolimus interferes with a variety of exocytosis-related events in cells of haematopoietic lineage (basophils, neutrophils and mast cells), but at concentrations which suppress T cell proliferation, tacrolimus does not modify mononuclear phagocyte function. Tacrolimus displays hepatotrophic properties, stimulating hepatic regeneration following hepatectomy, and confers hepatoprotective and renoprotective effects against ischaemia/reperfusion injury. Tacrolimus has a direct glomeruloconstrictive effect and on subacute administration reduces renal perfusion and glomerular flow. Tacrolimusinduced nephrotoxicity has variously been attributed to altered prostaglandin metabolism, lipid peroxidation of the plasma membrane, and enhanced endothelin secretion. In animal models of organ transplantation, tacrolimus has been shown to prolong survival of hepatic, renal, cardiac, small intestine, pancreatic and skin allografts, and to reverse cardiac and renal allograft rejection.

Pharmacokinetic Properties

Enzyme-linked immunoabsorbant assay (ELISA) employing a monoclonal anti-tacrolimus antibody has been used to quantify tacrolimus (and its immunoreactive metabolites) in biological fluids. Absorption of tacrolimus following oral administration is highly variable, as reflected in a peak plasma concentration (Cmax) of 0.4 to 5.6 μg/L after a single oral dosage of 0.15 mg/kg. Cmax values following intravenous infusion of tacrolimus 0.15 mg/kg over 2 hours ranged from 10 to 24 μg/L. Tacrolimus is highly lipophilic and undergoes extensive tissue distribution. In blood, tacrolimus is sequestered by erythrocytes, with the result that plasma drug concentrations are approximately 10 to 30 times lower than whole blood concentrations. Tacrolimus is metabolised extensively in the liver, primarily by demethylation and hydroxylation, with less than 1% of the parent compound being excreted unaltered in the bile and urine. Hepatic dysfunction is associated with elevated plasma concentrations of tacrolimus, prolongation of the plasma elimination half-life, and reduced plasma clearance.

Clinical Efficacy

The vast majority of investigations which evaluated the efficacy of tacrolimus as a rescue or primary immunosuppressive therapy in liver or kidney allograft recipients were presented at symposia and were only briefly reported or subsequently published to document symposia proceedings. The results of these studies should therefore be interpreted with caution as they have not been subjected to extensive peer review. Furthermore, there has only been one large study which evaluated the efficacy of tacrolimus as a rescue therapy in renal allograft recipients and there is a paucity of randomised investigations of tacrolimus versus cyclosporin as a primary immunosuppressant, particularly in renal transplantation.

In paediatric/adult patients experiencing liver allograft rejection or adverse effects associated with conventional immunosuppressive therapy who were subsequently treated with tacrolimus plus corticosteroids, patient survival was ⩾85% and graft survival exceeded 70% at initial follow-up (⩾2 months). These results were maintained in the longer term (≈9 to 18 months) in one study, although actuarial patient and graft survival rates were 70 or 72% and 50 or 70%, respectively, after 12 months in 2 others. Rescue therapy with tacrolimus was associated with histological and biochemical improvements in allograft function in a large proportion of patients, and this reflected in improvements in performance status when assessed in one study. Histological assessment of graft function revealed that prognosis was notably superior in patients with acute versus chronic rejection in one investigation; however, in another more detailed study, outcome was dependent on preconversion liver and kidney function, and on a history of retransplantation.

When administered as a primary immunosuppressant in combination with corticosteroids to patients who received a primary liver transplant, therapy with tacrolimus in the medium term (6 to 18 months) was associated with patient survival rates generally ⩾84% (although 63% was obtained in one study), and graft survival rates approaching or exceeding 80%. There were no significant differences in patient or graft survival rates for tacrolimus versus cyclosporin in the 2 largest randomised investigations (total patient numbers of 520 and 545), although both these parameters were numerically greater for tacrolimus in one of these studies (+4 to +5%). In the majority of the other comparative investigations evaluated, graft and patient survival rates were statistically and/or numerically greater with tacrolimus than with cyclosporin (+8 to +17% and +15 to +20%, respectively). Retransplantation rates were either similar or lower with tacrolimus compared with cyclosporin. Furthermore, in one small randomised investigation, 73% of cyclo-sporin-treated patients were switched to therapy with tacrolimus, and rejection accounted for the switch in approximately 75% of these recipients. Comparison of hospital costs of liver transplantation revealed that primary immunosuppression with cyclosporin was nearly twice as expensive as that with tacrolimus.

Although only assessed in one large investigation, tacrolimus has demonstrated efficacy as a rescue therapy when administered in combination with corticosteroids to kidney allograft recipients experiencing rejection despite optimum standard immunotherapy. Patient survival exceeded 90%, and 70% of patients were successfully converted after a mean follow-up of 10.6 months. Serum creatinine levels and the overall need for dialysis declined.

In adult or paediatric kidney allograft recipients, administration of tacrolimus as a primary immunosuppressant, plus corticosteroids, resulted in patient survival of ⩾90% and graft survival of ⩾70%, during follow-up periods of 1 to 21 months. In patients at lower risk of treatment failure, however, graft survival up to 1 year was noticeably greater (≈80%). Patient and graft survival rates did not differ significantly between patients receiving tacrolimus or cyclosporin, or those treated with tacrolimus in the presence or absence of azathioprine. Worthy of note was the efficacy of tacrolimus in recipients of paediatric en bloc allografts, in whom urological complications did not manifest, even in grafts from the smallest of donors.

The incidence of rejection with tacrolimus was largely reduced following rescue therapy, and was generally lower than that noted for cyclosporin when administered as a primary immunosuppressant therapy in liver allograft recipients. Notably, in the latter setting, the overall and refractory rejection incidence was significantly less in patients treated with tacrolimus versus cyclosporin in 2 large randomised investigations. Not surprisingly, the lower incidence of rejection noted for patients treated with tacrolimus generally reflected less need for adjunct immunotherapy (azathioprine, high dose steroids and antilymphocyte preparations) for the treatment of rejection episodes. Tacrolimus was also associated with a steroid-sparing effect, which resulted in lower maintenance steroid requirements when compared with cyclosporin. Indeed, steroid withdrawal was often possible for patients (notably children) treated with tacrolimus. The incidence of hypertension was also lower with tacrolimus in some (but not all) investigations when compared with cyclosporin, and tacrolimus was not associated with hypercholesterolaemia.

Tolerability

The variety of tacrolimus dosage regimens employed in clinical investigations has complicated interpretation of the tolerability profile of this drug. Indeed, its adverse effects have been pivotal in the temporal refinement of tacrolimus dosage regimens. Generally, toxicity is reduced by lowering the tacrolimus dosage, although such measures may not improve some reactions (such as the development of dysarthrias) which may be idiosyncratic or require multiple factors to emerge.

The clinical presentation and morphology of tacrolimus nephrotoxicity are identical to those of cyclosporin, and the incidence of this adverse effect is broadly similar for patients treated with either drug. The incidence of nephrotoxicity necessitating withdrawal from therapy was similar for tacrolimus and cyclosporin in a large randomised study when the former drug was administered at initial intravenous dosages ⩽0.06 mg/kg, but was greater when these initial dosages were exceeded. In another large study of similar design haemodialysis requirements were similar for tacrolimus and cyclosporin recipients. Acute nephrotoxicity (characterised by increased serum creatinine levels within 1 month of treatment), has occurred in most tacrolimus recipients and necessitated haemodialysis in up to about 25% of patients who received a liver allograft. Chronic nephrotoxicity (after 1 month of treatment) has been reported to occur in about 30 to 50% of patients. Nephrotoxicity may respond to a reduction in tacrolimus dosage, although reports differ as to the degree of correlation between plasma tacrolimus concentrations and renal function variables. In one study nephrotoxicity, assessed by histopathological changes in biopsy specimens, was recorded with trough whole blood tacrolimus concentrations within the currently accepted optimum range (≈ 15 to 20 μg/L). Mild hyperkalaemia, associated with low or low-normal renin and aldosterone levels commonly occurs with tacrolimus therapy, but usually responds to treatment with potassium-binding resins, potassium-restricted diets and/or fludrocortisone. Cyclosporin and tacrolimus appear to induce a similar incidence of nephrotoxicity, and although similar changes in serum creatinine levels occur with either drug following transplantation, adverse effects on glomerular filtration rate appear to occur less severely with tacrolimus in the long-term. Histopathological examination of renal allografts from patients experiencing rejection revealed some of the features associated with cyclosporin toxicity in patients treated with tacrolimus; however, the effect of prolonged tacrolimus administration on renal structural integrity with prolonged requires further study.

Infections have been reported to occur in ⩽50% of patients treated with tacrolimus, and were severe in 38% of the population studied. In clinical trials, tacrolimus was often associated with a numerical and/or statistical lower incidence of overall, severe, bacterial, viral or fungal infections when compared with cyclosporin. Post-transplant lymphoproliferative disorders apparently occur with a similar incidence among patients treated with either tacrolimus or cyclosporin (<2%).

Neurological adverse effects associated with post-transplant tacrolimus immunosuppression most commonly occur with intravenous administration and can be categorised as major (e.g. akinetic mutism, expressive aphasia, seizures, confusion requiring investigation, psychosis, encephalopathy, persistent coma) or minor (e.g. tremors, headache, sleep disturbances, nightmares, dysesthesias, photophobia) neurotoxicity. Major neurotoxicity has been reported in less than 10%, and minor neurotoxicity in about 20% of patients. In most cases tacrolimus-induced neurological effects resolve with dosage reduction or withdrawal from therapy. The incidence of neurotoxicity necessitating withdrawal from therapy was similar for tacrolimus and cyclosporin when the former drug was administered at initial intravenous dosages ⩽0.06 mg/kg in a large randomised study, but was greater when these initial dosages were exceeded.

Association of post-transplant hyperglycaemia with tacrolimus is confounded by the influence of perioperative events in the short term. With chronic administration (⩾3 months), hyperglycaemia requiring insulin therapy appears to vary temporally; up to 20% of patients require insulin at 6 months but as few as 5.5% require it after 1 year. The incidence of new-onset diabetes among paediatric allograft recipients treated with tacrolimus appears to be low (<2%). Insulin-dependent new-onset diabetes does not appear to occur more frequently with tacrolimus than with other immunosuppressive regimens, but the diabetogenic effect of this drug is likely to be as significant. Indeed, the incidence of hyperglycaemia was greater with tacrolimus when compared with cyclosporin in one large randomised investigation, although the converse was seen among children treated with either of these drugs in another.

Although hypertension is a common finding in transplant recipients, treatment with tacrolimus allows withdrawal of antihypertensive therapy from a significant portion of patients. Furthermore, cessation of antihypertensive therapy is generally more common with tacrolimus than with cyclosporin. Gingival hyperplasia and hirsutism, which are complications of therapy with cyclosporin, do not appear to be of significance among patients treated with tacrolimus. Furthermore, hypercholesterolaemia is apparently not a complication of tacrolimus therapy.

In common with cyclosporin, tacrolimus has been associated with rare instances of acute haemolytic anaemia; 8 of 1400 patients treated with the drug developed this phenomenon at one centre in the US.

Dosage and Administration

In hepatic or renal transplantation tacrolimus has usually been administered intravenously commencing after revascularisation of the graft and continuing until oral administration was feasible. However, the optimum dosage regimen for tacrolimus is continuing to be refined. Most recent experience in large randomised studies indicate that initial continuous intravenous dosages of ⩽0.1 mg/kg/day or 0.035 to 0.075 mg/kg/day should be employed, with subsequent initial oral dosages of 0.1 to 0.2 mg/kg/day. Preoperative administration of tacrolimus has been rare, although it has been given orally at 0.15 mg/kg (single dose) or intravenously at 0.15 mg/kg/12h for 2 days before renal transplantation. In the clinical setting dosage adjustments are made based on liver and kidney function, rejection status and trough tacrolimus concentrations in plasma or whole blood. Dosage requirements generally decline temporally, but long term therapy is necessary. Maintenance tacrolimus dosages expressed as a function of bodyweight are greater in children than in adults. A computer programme is available to select the optimum tacrolimus dosage based on patient characteristics.

Tacrolimus should not be administered with cyclosporin due to potential nephrotoxicity. In patients who simultaneously receive drugs which are metabolised by the cytochrome P450 IIIa enzyme system tacrolimus should be administered with caution.

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© Adis International Limited 1993

Authors and Affiliations

  • David H. Peters
    • 1
  • Andrew Fitton
    • 1
  • Greg L. Plosker
    • 1
  • Diana Faulds
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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