Tacrolimus

Abstract

Tacrolimus (FK-506) is an immunosuppressant agent that acts by a variety of different mechanisms which include inhibition of calcineurin. It is used as a therapeutic alternative to cyclosporin, and therefore represents a cornerstone of immunosuppressive therapy in organ transplant recipients. Tacrolimus is now well established for primary immunosuppression in liver and kidney transplantation, and experience with its use in other types of solid organ transplantation, including heart, lung, pancreas and intestinal, as well as its use for the prevention of graft-versus-host disease in allogeneic bone marrow transplantation (BMT), is rapidly accumulating. Large randomised nonblind multicentre studies conducted in the US and Europe in both liver and kidney transplantation showed similar patient and graft survival rates between treatment groups (although rates were numerically higher with tacrolimus-versus cyclosporin-based immunosuppression in adults with liver transplants), and a consistent statistically significant advantage for tacrolimus with respect to acute rejection rate. Chronic rejection rates were also significantly lower with tacrolimus in a large randomised liver transplantation trial, and a trend towards a lower rate of chronic rejection was noted with tacrolimus in a large multicentre renal transplantation study. In general, a similar trend in overall efficacy has been demonstrated in a number of additional clinical trials comparing tacrolimus-with cyclosporin-based immunosuppression in various types of transplantation. One notable exception is in BMT, where a large randomised trial showed significantly better 2-year patient survival with cyclosporin over tacrolimus, which was primarily attributed to patients with advanced haematological malignancies at the time of (matched sibling donor) BMT. These survival results in BMT require further elucidation. Tacrolimus has also demonstrated efficacy in various types of transplantation as rescue therapy in patients who experience persistent acute rejection (or significant adverse effects) with cyclosporin-based therapy, whereas cyclosporin has not demonstrated a similar capacity to reverse refractory acute rejection. A corticosteroid-sparing effect has been demonstrated in several studies with tacrolimus, which may be a particularly useful consideration in children receiving transplants. The differences in the tolerability profiles of tacrolimus and cyclosporin may well be an influential factor in selecting the optimal treatment for patients undergoing organ transplantation. Although both drugs have a similar degree of nephrotoxicity, cyclosporin has a higher incidence of significant hypertension, hypercholesterolaemia, hirsutism and gingival hyperplasia, while tacrolimus has a higher incidence of diabetes mellitus, some types of neurotoxicity (e.g. tremor, paraesthesia), diarrhoea and alopecia. Conclusion: Tacrolimus is an important therapeutic option for the optimal individualisation of immunosuppressive therapy in transplant recipients. Tacrolimus (FK-506) is a macrolide immunosuppressant that acts by a variety of different mechanisms which include inhibition of calcineurin. The drug inhibits T lymphocyte activation and transcription of cytokine genes including that for interleukin-2. Tacrolimus inhibits cell-mediated and, to a lesser extent, humoral immune responses. Cytokines produced by T helper (T_h)1 cells are preferentially suppressed over those produced by T_h2 cells. The mechanism of action of tacrolimus is largely similar to that of cyclosporin, but tacrolimus is 10 to 100 times more potent. The drugs both inhibit calcineurin but do so via formation of complexes with different immunophilins: tacrolimus binds to FK-506 binding protein 12, whereas cyclosporin binds to cyclophilin A. The drugs appear to differ in their effects on patterns of T_h2 cell cytokine expression and possibly some aspects of humoral immunity. Furthermore, lymphocyte sensitivity to the drugs may differ between patients. In animal models, tacrolimus had an organ-specific effect in stimulating hepatic regeneration after partial hepatectomy, and attenuated hepatic ischaemic or reperfusion injury. Tacrolimus does not appear to cause postoperative cholestasis in liver transplant recipients, and postoperative disturbances in biliary secretion and flow rates may recover more rapidly with tacrolimus than cyclosporin. Like cyclosporin, tacrolimus has nephrotoxic effects that appear to be mechanistically related to its immunosuppressive activity, possibly involving inhibition of calcineurin. Tacrolimus suppresses insulin production at the trans-criptional level and appears to be more diabetogenic than cyclosporin in some patients. In patients with liver transplants, tacrolimus reduced β cell secretory reserve, and was associated with significant insulin resistance and impaired β cell-α cell axis. Further clarification is required of the comparative effects of tacrolimus and cyclosporin on factors involved in cardiac transplant-associated coronary artery disease. Although tacrolimus has been associated with a lower incidence of positivity for anti-endothelial cell antibodies than cyclosporin, a higher incidence of pathological microvascular endothelial dysfunction has also been reported. Tacrolimus may have an in vitro antithrombotic effect. Findings have been conflicting regarding the comparative effect of tacrolimus and cyclosporin on endothelium-independent microcirculatory responses 1 year after cardiac transplantation. Tacrolimus and cyclosporin appear to have similar effects on most aspects of cardiac function in renal or liver transplant recipients. Like cyclosporin, the pharmacokinetic properties of tacrolimus can vary widely between individuals and dosage regimens are titrated according to whole-blood trough drug concentrations. Oral bioavailability of tacrolimus is about 20 to 25%, and food appears...