TACROLIMUS - A REVIEW OF ITS PHARMACOLOGY, AND THERAPEUTIC POTENTIAL IN HEPATIC AND RENAL-TRANSPLANTATION

Tacrolimus (FK 506) is a macrolide immunosuppressant which possesses s imilar but more potent immunosuppressant properties compared with cycl osporin, inhibiting cell-mediated and humoral immune responses. Like c yclosporin, tacrolimus demonstrates considerable interindividual varia tion in its pharmacokinetic profile. This has caused difficulty in def ining the optimum dosage regimen and has highlighted the usefulness of therapeutic drug monitoring. Most clinical studies with tacrolimus ha ve neither been published in their entirely nor subjected to extensive peer review; there is also a paucity of published randomised, investi gations of tacrolimus versus cyclosporin, particularly in renal transp lantation. Despite these drawbacks, tacrolimus has shown notable effic acy as a rescue or primary immunosuppressant therapy when combined wit h corticosteroids in adult and paediatric recipients following liver o r kidney transplantation. Indeed, graft salvage rates in patients expe riencing rejection or drug-related toxicity were greater-than-or-equal -to 50%, although data in renal transplantation are limited. Compared with cyclosporin as a primary immunosuppressant, tacrolimus showed com parable or greater patient/graft survival rates in liver allograft rec ipients (where cost savings associated with reduced hospitalisation co sts were evident in one study), and comparable patient/graft survival in patients following kidney transplantation. Worthy of note was the e fficacy of tacrolimus as a primary immunosuppressant in patients who r eceived en bloc kidney allografts. The incidence of rejection was larg ely reduced following rescue therapy with tacrolimus and was generally lower (notably for refractory rejection) than that observed for cyclo sporin, at least in liver allograft recipients. This was reflected in less need for adjunct immunotherapy including antilymphocyte preparati ons for the treatment of rejection episodes. The potential for reducti on or withdrawal of corticosteroid therapy with tacrolimus appears to be a distinct advantage compared with cyclosporin, and this may be enh anced by the reduced incidence of infectious complications and of hype rtension and hypercholesterolaemia reported by some investigators. In other respects, however, the tolerability profile of tacrolimus appear s to be broadly similar to that of cyclosporin. Against this backgroun d, preliminary data indicate that tacrolimus provides a valuable thera peutic alternative to retransplantation in patients experiencing liver or kidney graft rejection or drug-related toxicity. Pending confirmat ion of initial randomised studies and preliminary results from large r andomised investigations, tacrolimus may well be considered as an alte rnative primary immunosuppressant to cyclosporin in hepatic (particula rly) and renal transplantation. Furthermore, the steroid-sparing effec ts of tacrolimus, although of benefit to all patient groups, may prove to be of particular worth in children and in en bloc kidney recipient s. In these patients tacrolimus may well emerge as the drug of choice. Clearly, further experience in the clinical setting will help clarify the role of tacrolimus in transplantation surgery. Nevertheless, this new immunosuppressant has already demonstrated its usefulness as an a ddition to the limited immunotherapeutic options available to date.