Study and Therapy News

Tacrolimus was discovered in 1984 by the Fujisawa Pharmaceutical Company, based in Japan. It is structurally a macrolide, produced by Streptomyces tsukubaensis, a soil fungus originally found on Mount Tsukuba, Japan. The original research compound designation for tacrolimus was FK506, a name which is still frequently used in transplantation literature. Based on its immunomodulating properties, tacrolimus for systemic use by peroral or intravenous administration was initially developed to prevent organ rejection following allogenic liver or kidney transplantation. For these indications, tacrolimus was approved by the FDA, under the trade name Prograf®, for clinical use in the USA in 1994. In the Nordic countries Prograf was approved by the Swedish and Danish health authorities in 1995, and it has been available in all Nordic countries since 1997. The mechanism of action for tacrolimus when used systemically in transplantation is a direct inhibition of interleukin 2 (IL-2) transcription in T lymphocytes. This results in a decreased responsiveness of T lymphocytes to foreign antigens, and clinically tacrolimus is used as a baseline therapy in the immunosuppressive regimen following allogeneic solid organ transplantation, mainly liver and kidney. A large number of studies have demonstrated tacrolimus to be a highly effective agent for the prevention of organ rejection and for the rescue of patients experiencing acute and chronic rejection while on other immunosuppressive regimens. Additional clinical trials are ongoing to address the efficacy and safety of tacrolimus after allogeneic transplantation of heart, lung, intestines, pancreas and bone marrow. A comprehensive summary of the clinical efficacy and safety of systemic tacrolimus therapy in transplantation indications has recently been published (1). As with other drugs used to prevent allograft rejection, tacrolimus is associated with side effects when used systemically. Adverse events associated with systemic tacrolimus mainly concern the nervous system (e.g. tremor), gastrointestinal system (e.g. diarrhea) and urogenital system (increased creatinine). Generally, the side effects appear to be related to dose and blood concentrations. Immunosuppressive regimens are also known to increase the risk of infections and malignancies. In observational studies on the development of various tumours, skin tumours are the most commonly encountered type after liver transplantation (2, 3). There are observations indicating a lower incidence of skin tumour development on tacrolimus than on cyclosporine (2), but the majority of previous studies report the overall therapeutic immunosuppressive dose to be the most important risk factor rather than individual agents (4, 5).