Tacrolimus: a further update of its use in the management of organ transplantation

Abstract

Extensive clinical use has confirmed that tacrolimus (Prograf) is a key option for immunosuppression after transplantation. In large, prospective, randomised, multicentre trials in adults and children receiving solid organ transplants, tacrolimus was at least as effective or provided better efficacy than cyclosporin microemulsion in terms of patient and graft survival, treatment failure rates and the incidence of biopsy-proven acute and corticosteroid-resistant rejection episodes. Notably, the lower incidence of rejection episodes after renal transplantation in tacrolimus recipients was reflected in improved cost effectiveness. In bone marrow transplant (BMT) recipients, the incidence of tacrolimus grade II-IV graft-versus-host disease was significantly lower with tacrolimus than cyclosporin treatment. Efficacy was maintained in renal and liver transplant recipients after total withdrawal of corticosteroid therapy from tacrolimus-based immunosuppression, with the incidence of acute rejection episodes at up to 2 years' follow-up being similar with or without corticosteroids. Tacrolimus provided effective rescue therapy in transplant recipients with persistent acute or chronic allograft rejection or drug-related toxicity associated with cyclosporin treatment. Typically, conversion to tacrolimus reversed rejection episodes and/or improved the tolerability profile, particularly in terms of reduced hyperlipidaemia. In lung transplant recipients with obliterative bronchiolitis, conversion to tacrolimus reduced the decline in and/or improved lung function in terms of forced expiratory volume in 1 second. Tolerability issues may be a factor when choosing a calcineurin inhibitor. Cyclosporin tends to be associated with a higher incidence of significant hypertension, hyperlipidaemia, hirsutism, gingivitis and gum hyperplasia, whereas the incidence of some types of neurotoxicity, disturbances in glucose metabolism, diarrhoea, pruritus and alopecia may be higher with tacrolimus treatment. Renal function, as assessed by serum creatinine levels and glomerular filtration rates, was better in tacrolimus than cyclosporin recipients at up to 5 years' follow-up.

Conclusion: Recent well designed trials have consolidated the place of tacrolimus as an important choice for primary immunosuppression in solid organ transplantation and in BMT. Notably, in adults and children receiving transplants, tacrolimus-based primary immunosuppression was at least as effective or provided better efficacy than cyclosporin microemulsion treatment in terms of patient and graft survival, treatment failure and the incidence of acute and corticosteroid-resistant rejection episodes. The reduced incidence of rejection episodes in renal transplant recipients receiving tacrolimus translated into a better cost effectiveness relative to cyclosporin microemulsion treatment. The optimal immunosuppression regimen is ultimately dependent on balancing such factors as the efficacy of the individual drugs, their tolerability, potential for drug interactions and pharmacoeconomic issues.