Experience with cyclosporine.

The introduction of cyclosporine (CyA) was a landmark in transplantation, and in the two decades that have followed, enormous experience has been acquired in its use. This has led to both an understanding of its mechanism, pharmacokinetics and toxicity, and the continued evolution of its clinical application. Many of the initial complexities related to the hydrophobic nature of the molecule, and its variable absorption were addressed by the introduction of the microemulsion formulation Neoral. Despite this, the therapeutic window for CyA remains narrow, and therapeutic drug monitoring, recognized early after its introduction, is essential. However, this too has been redefined with single-point, 2-hour, postdose monitoring being demonstrated to correlate better with dose and outcome than the traditional 12-hour trough level. Implementation of such techniques may impact on efficacy and the long-term effects of nephrotoxicity. The need to gain experience with new facets of CyA is likely to continue. In particular, the use of reduced doses to minimize nephrotoxicity during long-term management has produced favorable early results. Furthermore, in the near future the availability of generic CyA formulations will increase. It cannot be assumed that these will be bioequivalent to the current preparations, and modifications of therapy, outside of current experience, may be required. However, if 20 years of CyA usage has taught us anything, it is that different formulations may have very different biological behavior, and at least this situation can be approached with a caution gained from long experience.