Cyclosporin - An updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoral((R)))(1) in organ transplantation

Cyclosporin is a lipophilic cyclic polypeptide immunosuppressant that inter feres with the activity of T cells chiefly via calcineurin inhibition. The original oil-based oral formulation of this drug (Sandimmun (R))(1) was cha racterised by high intra- and interpatient pharmacokinetic variability, wit h poor bioavailability in many patients; a novel microemulsion formulation (Neoral (R))(1) was therefore developed to circumvent these problems, Studi es show increases, attributable chiefly to improved absorption in patients who absorb the drug only poorly from the original formulation, in mean syst emic exposure to cyclosporin with the microemulsion, with no clinically sig nificant differences in tolerability or drug interaction profiles. Cyclosporin microemulsion is at least as effective as the oil-based formula tion in renal, liver and heart transplant recipients, with trends towards d ecreased incidence of acute rejection with the microemulsion formulation in some (statistically significant in a few) trials. Cyclosporin microemulsio n and tacrolimus appear to have similar efficacy in preventing acute reject ion episodes in most renal, pancreas-kidney, liver and heart transplant rec ipients. However, there are indications of superior efficacy for tacrolimus in some trials, particularly in the prevention of severe acute rejection a nd in Black transplant recipients. Current 12-month data also indicate equi valent efficacy of sirolimus in renal transplantation. Conversion from the oil-based to microemulsion formulation in stable renal, liver and heart transplant recipients is achievable with no change in acut e rejection rates. The addition of an anti-interleukin-2 receptor monoclona l antibody and/or mycophenolate mofetil to cyclosporin microemulsion plus c orticosteroids decreases rates of acute rejection; corticosteroid withdrawa l without increased acute rejection rates was also achieved on the addition of these agents in some trials. Pharmacoeconomic analyses have shown savings in direct healthcare costs in kidney or liver transplantation when cyclosporin microemulsion is used in p reference to the oil-based formulation, although studies incorporating indi rect costs or expressing costs in terms of therapeutic outcomes are current ly unavailable. Conclusions: The introduction of cyclosporin microemulsion has consolidated the place of the drug as a mainstay of therapy in all types of solid organ transplantation; research into optimisation of outcomes through more effec tive therapeutic monitoring in patients receiving this formulation is ongoi ng. Several novel immunosuppressants have been introduced in recent years: further clinical and pharmacoeconomic research will be needed to clarify th e relative positioning of these agents, particularly with respect to specif ic patient groups. Other new drugs (basiliximab/daclizumab and mycophenolat e mofetil) offer particular advantages when used in combination with cyclos porin.