FDA Approval of Tacrolimus for Primary Immunosuppression in Cardiac Transplantation

The FDA has recently approved the use of tacrolimus for primary immunosuppression in heart transplantation. An article published in Expert Review of Clinical Immunology examines the clinical evidence behind this approval. This review confirms the efficacy of tacrolimus for immunosuppression in heart transplantation, backing previously established efficacy in other solid organ transplants. A number of clinical trials comparing tacrolimus to the older calcineurin inhibitor cyclosporine A have demonstrated tacrolimus to be comparable in terms of survival and incidence of cardiac allograft vasculopathy. It is also thought that tacrolimus is associated with an overall improvement in acute allograft rejection and adverse effects profile when compared to cyclosporine A. In particular the rates of hypertension and dyslipidaemia were less than observed with cyclosporine A. There is compelling evidence that points to tacrolimus plus mycophenolate mofetil and a corticosteroid as the most effective regimen for immunosuppression in cardiac transplantation. It is believed that future developments in modified release dose forms may provide further benefits in relation to patient adherence.

The introduction of the first calcineurin inhibitor cyclosporine A (CsA) to the immunosuppressive regimen in solid organ transplantation resulted in a dramatic increase in patient survival. One of the drawbacks of CsA therapy however is the relatively high incidence of serious adverse effects. These effects include hypertension, dyslipidaemia, nephrotoxicity and hepatotoxicity. More recently another calcineurin inhibitor, tacrolimus has become available. Tacrolimus has been used successfully in renal, hepatic and lung transplantation to the extent that it is used in approximately half of such transplants. Tacrolimus has also been evaluated in a number of large clinical trials against CsA for cardiac transplantation. The outcomes of these trials have shown favourable results for tacrolimus and lead to the FDA approving tacrolimus for use in cardiac transplantation.Tacrolimus has been evaluated against CsA with respect to several outcomes. Outcomes of particular interest include survival, efficacy at managing rejection episodes and adverse effects. With respect to survival rate analysis of at least seven clinical trials from 1997 onwards was conducted. These studies have all shown strong evidence that tacrolimus is comparable to CsA in terms of survival and cardiac allograft vasculopathy. In terms of acute rejection episodes however, it appears that tacrolimus is superior to CsA. It is thought that pharmacokinetic differences between the two drugs may be responsible for this effect. It is suggested that steady state plasma levels observed with tacrolimus are a more accurate representation of area under the curve concentrations then that seen with CsA, thus making dose selection more accurate.In relation to adverse effects it also appears that there is a large difference in incidence between the two drugs. A number of clinical trials have shown that tacrolimus has a significantly lower rate of hypertension and dyslipidaemia at one year compared to CsA. In addition one study which followed patients randomised to either tacrolimus or CsA over five years showed a lower average serum creatinine level in the tacrolimus group. This finding requires further investigation but points to a potentially lower rate of drug induced renal insufficiency in long term use. A number of studies comparing the efficacy of different treatment regimens were also examined in this review. The most effective immunosuppression regimen in cardiac transplantation to date appears to be a combination of tacrolimus plus mycophenolate mofetil (MMF) and a corticosteroid. One such study reported a significantly lower rate of rejection at 23.4% for tacrolimus plus MMF compared to 36.8% for CsA plus MMF at one year. Further investigation is needed to confirm these findings over a longer time period.Despite a lower rate of acute rejection, favourable adverse effects profile and comparable survival compared to CsA therapy with tacrolimus is not without hazard. Tacrolimus is still associated with some severe side effects and treatment may be complicated due to its variable inter and intra subject absorption. Due to these difficulties further investigation of various regimens are warranted. Investigations underway include studies assessing a sustained release formulation, a low dose regimen and a clinical trial investigating the use of tacrolimus as a sole agent. It is hoped the sustained release formulation will increase patient adherence and improve absorption. In spite of some limitations common to all immunosuppressive therapies tacrolimus has a valuable role in cardiac transplantation for the foreseeable future.Reference: