Tacrolimus is effective as part of triple-drug maintenance therapy in lung transplantation

Tacrolimus has been used successfully as part of triple-drug maintenance in a range of solid organ transplants. Following the increasing use of tacrolimus in lung transplantation there has been a need to evaluate its efficacy with respect to this indication. An article published in Drugs reviews the evidence to date for tacrolimus as part of an immunosuppressive regimen in lung transplantation. This review establishes tacrolimus as part of an effective triple-drug regimen in lung transplantation. From the current clinical evidence it appears that tacrolimus is comparable to cyclosporine A in terms of both infection and survival at two years. Tacrolimus may also be associated with a lower incidence of bronchiolitis obliterans syndrome and acute or recurrent rejection events that require hospitalisation compared to cyclosporine A. Further large randomised controlled trials are required to confirm these promising results.

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. Since this time another calcineurin inhibitor, tacrolimus has become available and has seen increasing clinical use. The use of tacrolimus in heart, liver and kidney transplantation has been extensively reviewed and found to have some clear advantages over therapy with CsA. Some of the advantages of a drug regimen including tacrolimus reported by such investigations included a lower incidence of adverse effects and fewer acute rejection events. The current immunosuppressive regimens used in lung transplantation are based on these data from other solid organ transplantation and small clinical trials in lung transplant recipients. Therefore there has been a need to review the available data for lung transplantation to evaluate the regimens in current use.

One of the authors, Clinical Associate Professor Gregory Snell, said that his article, “describes the major lung transplant studies over the last 20 years. Trials have actually proved difficult to design, complete and interpret and in 2008 most clinical lung transplant units utilise protocols based on experience and other solid organ transplants; renal and cardiac in particular. Notwithstanding, the lung has some unique immunological features and unique solutions, such as inhaled immunosuppressant therapies, that may yet prove efficacious against lung acute and chronic allograft rejection.”

Tacrolimus was evaluated against CsA with respect to several outcomes. Of particular relevance were the occurrence of opportunistic infection and bronchiolitis obliterans syndrome (BOS). It is thought that if the incidence of BOS in particular can be reduced, then survival rates may be significantly increased.

The majority of regimens in current clinical use include a calcineurin inhibitor, an antimetabolite and a corticosteroid as part of triple drug therapy. A review of available clinical data suggest that tacrolimus is comparable to CsA in terms of both infection and survival rates at two years. In terms of adverse effects, this review also supports the evidence that tacrolimus is better tolerated than CsA when administered orally. In addition, the current clinical evidence also reveals that tacrolimus may be associated with a lower incidence of bronchiolitis obliterans syndrome and a significantly lower rate of acute or recurrent rejection events requiring hospitalisation compared to cyclosporine A. In a study where transplant recipients were randomised to receive either tacrolimus or CsA the incidence of BOS was 22% for the tacrolimus group compared to 38% in those receiving CsA. This result is encouraging, however, requires further investigation to evaluate its impact on long term survival.

In terms of the most effective maintenance drug regimen it appears that tacrolimus can be combined with either mycophenolate mofetil or azathioprine and a corticosteroid with equal efficacy. This result is in contrast to current clinical practice where mycophenolate mofetil is considered the preferred antimetabolite and this highlights the need for continuing research. As well as having benefits as maintenance therapy, tacrolimus appears to be highly effective as switch over therapy. One large randomised controlled study involving lung transplant recipients experiencing acute or chronic rejection showed that after switching from CsA to tacrolimus the incidence of recurrent rejection events and BOS was significantly reduced. This finding is of particular relevance due to the high incidence of acute (50%) and chronic rejection (45%) in lung transplantation.

Despite a number of advantages including a lower rate of acute rejection, favourable adverse effects profile and decreased incidence of BOS compared to CsA, therapy with tacrolimus is not without hazard. Tacrolimus is still associated with some significant toxicities, particularly if administered intravenously. Due to the small number of clinical trials specific to lung allograft transplantation further investigation of tacrolimus is warranted. Further evaluation of drug regimens with respect to choice of antimetabolite is also required; as preliminary investigation has revealed that results from other transplantation studies do not always apply to lung transplantation. In spite of some limitations common to all immunosuppressive therapies tacrolimus is confirmed as an effective therapy in lung transplantation for the foreseeable future.

(Source: Snell G, Westall G. Immunosuppression for Lung Transplantation: evidence to date. Drugs. 2007; 67 (11): 1531-1539)