Tacrolimus

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Abstract
Tacrolimus (FK 506) has been evaluated as immunosuppressive therapy in patients with a variety of solid organ and other transplants. Extensive data have now confirmed its efficacy as primary or rescue therapy in renal and hepatic transplantation. In prospective and historically controlled studies of primary therapy, tacrolimus generally demonstrated greater efficacy than the conventional formulation of cyclosporin for preventing episodes of acute rejection and allowed reduction of corticosteroid use. Chronic rejection rates were also significantly lower with tacrolimus in a large randomised liver transplantation trial. However, patient and graft survival rates were similar in both treatment groups (although numerically larger in adults with liver transplants). In children, rejection rates and corticosteroid requirements were usually lower with tacrolimus and patient and graft survival were generally similar with the 2 immunosuppressants. The finding of reduced corticosteroid requirements with tacrolimus may be of particular benefit in prepubertal children, who are still growing. A small amount of evidence has also accumulated regarding the use of tacrolimus as primary therapy in patients who have undergone bone marrow or heart and/or lung transplantation. Data are not conclusive, particularly in children, but tacrolimus appears to be useful for treating patients who have undergone these organ transplantations and may be associated with a lower incidence of obliterative bronchiolitis than cyclosporin in the latter group. Potential efficacy has also been shown in a limited number of patients with pancreas or pancreas-kidney, pancreatic islet and intestinal or multivisceral transplants, and in children who have undergone heart or heart-lung transplantation. Tacrolimus also has a use as rescue therapy in bone marrow, heart, lung and pancreatic transplantation, but data are currently insufficient for conclusions to be made. However, these results support the need for further study in these populations. Adverse effects occurring during tacrolimus therapy are generally of the type common to all immunosuppressive regimens. However, diabetes mellitus, neurotoxicity and nephrotoxicity are more common in tacrolimus than cyclosporin recipients. Hyperlipidaemia, hypertension, hirsutism and gingival hyperplasia are more common with cyclosporin. In 2 large multicentre clinical trials (US liver and European renal), tacrolimus was discontinued more frequently during the first year because of adverse events. However, the tolerability of tacrolimus appears related to dosage, improving as the dose is reduced. Tacrolimus should be considered an effective primary immunosuppressant in renal and hepatic transplantation. The drug is also a useful agent for rescue therapy in patients experiencing rejection or poor tolerability to cyclosporin. Thus, tacrolimus provides the clinician with an effective option for patients requiring immunosuppression and, with a different tolerability and efficacy profile to cyclosporin, it will better allow the tailoring of therapy to meet the needs of individual patients. Although structurally unrelated, tacrolimus (FK 506) and cyclosporin have similar and well characterised cellular effects. Tacrolimus exerts potent inhibitory effects on T lymphocyte activation. It binds specifically to immunophilins termed FK 506 binding proteins (FKBP), and signal transduction pathways in T cells are interrupted by the tacrolimus-FKBP12 complex. At in vitro concentrations 10 to 100 times lower than that of cyclosporin, tacrolimus inhibits transcription of early T cell activation genes for interleukin (IL)-2 and other growth-promoting cytokines, tumour necrosis factor (TNF)-α and proto-oncogenes; it also suppresses the expression of IL-2 and IL-7 receptors. Tacrolimus also inhibits the mixed lymphocyte reaction, generation of cytotoxic T cells and T cell-dependent B cell activation. The secondary proliferation of activated T cells in response to IL-2 is not inhibited by tacrolimus, nor does the drug interfere with antigen presentation or modify mononuclear phagocyte or natural killer cell function. Tacrolimus may differ from cyclosporin with regard to its effects on transforming growth factor (TGF)-β, high levels of which have been implicated in chronic renal allograft rejection. Whereas cyclosporin increases levels of TGF-β, tacrolimus does not seen to greatly alter these levels in patients with renal allografts. Tacrolimus may also inhibit cellular activities such as nitric oxide synthetase activation, cell degranulation and apoptosis, and potentiate the action of glucocorticoids. Nephrotoxicity is a serious adverse effect of both tacrolimus and cyclosporin. These agents produce virtually indistinguishable clinical and histological changes. Most patients treated with tacrolimus develop elevated serum creatinine levels, and although dosage adjustment may reduce nephrotoxicity, whole-blood drug concentrations do not correlate well with renal function. In patients with renal allografts, early morphological markers of tacrolimus-induced nephrotoxicity include tubular and myocyte vacuolation whereas long term changes include interstitial fibrosis and arteriolar hyalinosis. Increased endothelin levels have been implicated in post-transplant renal vasoconstriction. Marked reductions in biliary acid secretion and bile flow in T-tube bile were seen in the immediate post—liver transplantation period in patients receiving either tacrolimus or the conventional formulation of cyclosporin. However, biliary secretion rates increased to normal levels with time and, in 1 report, improvement was faster with tacrolimus than with cyclosporin. In animals, tacrolimus stimulated hepatic regeneration after partial hepatectomy. This effect was organ specific and was not seen in animals after partial nephrectomy or intestinal resection. Immunosuppressive therapy is associated with diabetogenic effects. Although tacrolimus has also been shown to produce these effects (see tolerability summary), the exact mechanism(s) of action remains to be elucidated. In animals, tacrolimus inhibited insulin gene transcription in vitro, possibly via interruption of a calcium-mediated signalling pathway. In renal or hepatic transplant recipients, tacrolimus generally caused significantly smaller changes in total and low density lipoprotein cholesterol than cyclosporin. Assessment of the pharmacokinetics of tacrolimus is greatly affected by the biological fluid analysed, the analytical method used and the duration of study. Whole blood appears to be the most appropriate medium for assessing the pharmacokinetics of tacrolimus. Absorption of tacrolimus is variable after oral administration and oral bioavailability is poor. In most patients, maximum plasma or blood concentrations are reached after about 0.5 to 1 hour, although some patients have a flat absorption profile (overall mean time to maximum concentrations of about 2 hours). Complete biliary diversion or addition of bile salts does not appear to have a significant effect on the oral bioavailability of tacrolimus. Therefore, oral therapy does not need to be overlapped with intravenous therapy in adults, as is the case for the conventional formulation of cyclosporin. Tacrolimus is highly bound to plasma proteins, primarily α1-acid glycoprotein and albumin. It also binds to erythrocytes and lymphocytes. High concentrations of tacrolimus are detected in organs such as the lungs, spleen, heart, kidney, pancreas, brain, muscle and liver in animals, but the drug has not been detected in the CSF. Tacrolimus is mainly metabolised in the liver (and to a lesser extent, the gut), by the cytochrome P450 CYP3A4 isoenzyme, to at least 15 metabolites. Less than 1% of an intravenous dose of tacrolimus undergoes urinary excretion as unchanged drug, with renal clearance accounting for 70%) and patient survival (>80%) rates at 1 year and retransplantation rates that do not differ significantly from those with cyclosporin. Likewise, after 3 and 5 years graft and patient survival rates do not differ significantly between tacrolimus and cyclosporin (although rates are numerically higher with tacrolimus). However, a large randomised study demonstrated a trend toward improved 3-year patient survival with tacrolimus. Individual studies of tacrolimus have reported graft and patient survival rates of 64.5 and 71.1%, respectively, at a mean follow-up of 78 months and, in US veterans (a high-risk group), 77 and 84% at 4 years. Tacrolimus offers several advantages over cyclosporin, such as significantly lower acute and refractory rejection rates, a steroid-sparing effect and earlier conversion to oral therapy. Indeed, refractory rejection occurred about 5 times more often with cyclosporin. Additionally, fewer patients receiving tacrolimus are switched to the alternative therapy because of rejection. Chronic rejection rates were also significantly lower during tacrolimus therapy than during cyclosporin therapy in 1 large multicentre trial. Chronic hepatitis C virus (HCV) infection with cirrhosis is a major indication for liver transplantation and its recurrence, which occurs in up to half of graft recipients after transplantation, may be associated with a poor prognosis. Patient and graft survival rates in a randomised US multicentre study did not differ between patients with HCV given tacrolimus and those given cyclosporin at 3 years. However, at 5 years, the patient survival rate was significantly higher in patients with HCV receiving tacrolimus than in those receiving cyclosporin. A small randomised trial and 2 nonrandomised comparisons have demonstrated higher rates of acute and steroid-resistant rejection in patients with HCV receiving tacrolimus, and in 1 trial cumulative 1 — to 7-year survival was higher with cyclosporin. Chronic hepatitis B virus (HBV) infection recurs in almost all patients after transplantation and indicates a very poor outcome. Survival was 73% at a median of 24 months (31 of the 57 survivors had HBV recurrence) in 78 patients with HBV liver disease who received tacrolimus plus corticosteroids as primary immunosuppression in 1 retrospective analysis. When tacrolimus was compared with cyclosporin in small trials, somewhat higher rates of acute rejection (52 vs 36.5%) and decreased survival rates were seen with tacrolimus. Analysis of a subgroup of patients with fulminant hepatic failure from the randomised prospective European trial revealed similar graft and patient survival rates in tacrolimus (n = 32) and cyclosporin (n = 23) recipients but lower rates of acute and chronic rejection with tacrolimus. Tacrolimus has an established role as rescue therapy in hepatic allograft recipients with steroid-resistant acute or chronic rejection or drug toxicity. Graft survival is ≥65% and patient survival is >75% at 1 year in patients with acute or chronic rejection who receive tacrolimus rescue therapy. Graft and patient survival rates in patients with chronic rejection appear to be close to those seen overall in patients receiving tacrolimus rescue for any reason. Long term (6 years) graft and patient survival rates were about 50% in 1 study. The rate of graft survival in patients with chronic rejection is halved if total bilirubin levels are high (≥60 mg/L). Similar results to those found in adults have been reported in children, although evidence is less substantial in this population. In children receiving tacrolimus, 1-year graft survival rates of ≥70% are achieved and patient survival rates are ≥80%. 78% of children receiving tacrolimus did not need steroids at 5 years at the University of Pittsburgh. Patient and graft survival rates in children receiving tacrolimus rescue therapy are similar to those seen in adults, with 1-year graft and patient survival rates of >70 and about 80%, respectively. The longest follow-up information available (5 years) shows a graft survival rate of 66.5%, with steroids withdrawn in 84% of children. In smaller studies, the response to rescue therapy with tacrolimus was generally good in children with acute rejection but poor in those with chronic rejection. Renal Transplantation: Tacrolimus is an effective immunosuppressant for patients who have undergone renal transplantation. In 395 patients, the addition of azathioprine to a tacrolimus plus prednisone regimen did not increase 1- and 2-year survival rates (actuarial patient survival rates were ≥90% and graft survival rates were ≥79% for both regimens). Three-year graft survival rates were higher in patients given tacrolimus and prednisone than in those who received all 3 agents (84 vs 76%). Graft and patient survival is greater in individuals maintained on steroid-free immunosuppressive regimens than in those requiring steroids. 49% of tacrolimus recipients with successful transplants were weaned from corticosteroids at 20 months and 69% at 33 months in 1 trial. Graft origin (from living related donors or cadavers) does not appear to significantly alter 3-year patient or graft survival; however, 2-year results of another trial showed a cadaveric donor to be a risk factor for rejection. Graft and patient survival rates at 1 year were similar with cyclosporin- and tacrolimus-based regimens, but acute or corticosteroid-resistant rejection occurred less frequently with tacrolimus. Chronic rejection rates did not differ significantly between tacrolimus and cyclosporin recipients, and about 12.5% of grafts failed in each treatment group. Tacrolimus is effective as rescue therapy for patients who have refractory acute renal allograft rejection episodes during cyclosporin prophylaxis. Rates of graft survival are about 75% and patient survival was >90% at 1 and 2 years. The success of tacrolimus rescue therapy is likely to be influenced by the level of pre-conversion kidney function and the time to tacrolimus conversion. Although low serum creatinine levels are predictive of a better outcome, poor renal function does not prevent success. The steroid-sparing effect of tacrolimus is also demonstrated during rescue therapy. Very good efficacy has been demonstrated for tacrolimus therapy in children, with 1-year patient and graft survival rates reported as 100% and >90%, respectively, during tacrolimus-based double or triple therapy. These rates were similar to those obtained in historical controls given cyclosporin. Although 1 trial showed acute rejection to be more common in tacrolimus recipients than in patients receiving cyclosporin, more recent data suggests that the acute rejection rate with tacrolimus has decreased as experience with the drug has increased. Graft origin does not influence efficacy. Steroid withdrawal was possible in >70% of children during tacrolimus prophylaxis. Few data are available concerning use of tacrolimus as rescue therapy in paediatric patients with renal allografts, although they do suggest that the drug has efficacy in reversing rejecdon in these patients. Thoracic Organ Transplantation: In patients with heart transplants enrolled in prospective trials, survival rates were similar with tacrolimus- and cyclosporin-based regimens, but tacrolimus was generally associated with a lower rate of acute rejection. Survival was about 90% at 1 year and about 75% at 5 years with both treatments. The percentage of patients free from coronary angiopathy was also similar with both treatments. When compared with patients who received a cyclosporin regimen that did not include antilymphocyte antibody agents, tacrolimus recipients had a lower rate of acute rejection, fewer associated steroid boluses and fewer episodes of acute rejection requiring lympholytic treatment per 100 patient-days in the largest trial in heart transplantation. In contrast, these differences were not detected when tacrolimus was compared with a cyclosporin regimen that did include induction with an antilymphocyte antibody agent in the same study. Limited evidence suggests that tacrolimus is effective for treating episodes of acute rejection refractory to cyclosporin. Small numbers of patients with intractable episodes of acute rejection during cyclosporin therapy responded to conversion to tacrolimus treatment. The actuarial survival rate and number of individuals completely free of acute rejection in a retrospective analysis of patients with acute rejection refractory to cyclosporin was higher with tacrolimus than with muromonab CD3. Data are scarce concerning use of tacrolimus in children undergoing heart transplantation. The most complete report available indicates an overall survival rate of 92% perioperatively and 82% at 1 and 3 years in 26 children (10 with cardiomyopathy, 16 with congenital heart disease) receiving primary immunosuppression with tacrolimus and low-dose corticosteroids. In a retrospective comparison with cyclosporin-based triple therapy and antithymocyte globulin induction, the actuarial rate of freedom from rejection (grade 3A or higher) was greater with tacrolimus therapy at 3 and 6 months. 85% of tacrolimus recipients and no cyclosporin recipients were weaned from steroids. Tacrolimus has also been successfully used as rescue therapy in small numbers of children with persistent grade 2, 3A or 3B rejection during cyclosporin therapy. Tacrolimus may offer an advantage over cyclosporin in reducing the risk of obliterative bronchiolitis (chronic rejection) in patients undergoing lung transplantation. It may also be associated with a lower rate of acute rejection episodes. However, in a randomised trial, 1- and 2-year patient survival rates did not differ between tacrolimus and cyclosporin. Case reports also suggests that tacrolimus is effective as rescue therapy in patients with lung or heart-lung transplants who experience acute rejection during cyclosporin therapy. The drug may also be beneficial in children who have undergone lung or heart-lung transplantation, although experience is too limited for any conclusions to be drawn. Pancreas or Pancreas-Kidney Transplantation: 18-month results from 250 patients suggest the drug is effective as primary therapy in pancreas transplantation. Rejection-associated graft loss was low in this series of patients who underwent pancreatic transplantation with or without kidney or BMT. Patient and pancreas graft survival rates were 95 and 85% at 18 months in 215 patients who did not undergo BMT (concurrent BMT reduced these rates). Results of indirect comparisons suggest that rejection is less frequent and graft survival is higher with tacrolimus than with cyclosporin, particularly in patients who have undergone simultaneous kidney and pancreas transplantation. As rescue therapy for rejection, tacrolimus produces a high rate of graft salvage: 18-month overall patient and pancreas graft survival rates of 92 and 80% have been reported. Patients experiencing cyclosporin nephrotoxicity have also benefited from tacrolimus therapy. Pancreatic Islet Transplantation: Grafting of pancreatic islet cells to replace the endocrine function of the pancreas is an alternative to whole pancreas transplantation. However, this procedure is still experimental in humans and, understandably, experience with tacrolimus is limited. Nonetheless, some success (e.g. stabilisation of diabetes or withdrawal of insulin) has been achieved in small numbers of patients with insulin-controlled diabetes mellitus who received intrahepatic islet allografts with tacrolimus immunosuppression. Intestinal With or Without Other...