Cyclosporin microemulsion - A guide to usage and monitoring

The oral bioavailability of cyclosporin from its original formulation (Sand-immun(R)) is relatively poor, and there is substantial variability in the extent and immun kinetics of absorption from this formulation. The variability in exposure to cyclosporin, even when therapy is optimised by reference to predose (trough) cyclosporin concentrations in blood, is associated with poor efficacy. In an effort to improve the oral bioavailability of cyclosporin, and to reduce variability in absorption, a new formulation has been developed (Neoral(R)). Results comparing the 2 formulations in Volunteers and transplant patients show more dose-linear kinetics and a consistently higher relative bioavailability for the new formulation, as well as a shorter and more reproducible time to maximum concentration. There is also a closer relationship between total exposure to the drug, as measured by the area under the concentration-time curve, and the trough concentration. In studies extending over a period of more than 1 year in renal transplant patients, both stable and de novo transplanted, the use of the new formulation has been associated with a lower total dose (by 10 to 15%) compared with the original formulation, and stabilisation of the dosage has been achieved more easily following an initial 1:1 conversion from the old to the new formulation. Despite the lower dosages with the new formulation, on average patients are exposed to more cyclosporin, although an increase in cyclosporin-related toxicity does not seem to be a problem. Some patients absorb the new formulation substantially better than the old formulation, and could be at risk of cyclosporin toxicity when converted to the new formulation. For this reason, more frequent blood concentration monitoring is advisable when patients are converted from the old formulation to the new, especially for those patients receiving relatively high dosages of the old formulation prior to conversion. The pharmacokinetic advantages of the new formulation observed in renal transplant patients have also held for other transplant settings and in patients receiving the drug for autoimmune indications. There are particular advantages for liver transplant patients, since the new formulation is less dependent on the presence of bile to aid absorption, so that oral therapy can be used in place of intravenous therapy from the time of transplantation. There are also substantial benefits for patients with cystic fibrosis. Whether the pharmacokinetic advantages of the new formulation are associated with gains in clinical efficacy is not established. Some preliminary studies have shown a trend towards a lower incidence of graft rejection in de novo kidney transplant patients receiving the new formulation, but this has not been noted in all studies. The implications of the new formulation for cyclosporin monitoring are that its more predictable absorption kinetics should reduce the number of trough concentration measurements needed to establish the optimal dosage, and that the measured concentrations should be more reflective of total drug exposure.