ABSTRACT
The revolution in organ transplantation began in the early 1980s with the discovery of a powerful, yet selective, immunosuppressive agent, cyclosporine. Later, tacrolimus, sirolimus, mycophenolic acid and everolimus were introduced and all continue to be used widely with great success in reducing the risk for organ rejection. These agents (see Figure 14.1 for structures) or their analogues are also being used to alleviate symptoms of auto-immune disease, to treat cancer, to reduce scar tissue formation around drug-eluting stents, and a variety of other applications. However, success with cyclosporine, and the other innovator agents that followed, has been achieved with a common belief in the benefits of therapeutic drug monitoring (TDM). These agents, except possibly mycophenolic acid, are critical dose drugs; that is, they exhibit narrow therapeutic ranges that overlap subtherapeutic and toxic indices. Moreover, individualized tailoring of drug regimen and dosage is required because of their wide intra-and interindividual pharmacokinetic variabilities that are due, in part, to type of transplant, time after transplant, race, concomitant drugs, and other factors. Thus, estimation of drug level is either required or recommended for each of these agents and TDM is critical to achieve optimal clinical outcome. Numerous task forces, expert panels and consensus panels have been convened to review issues related to TDM of these immunosuppressive agents and to make recommendations for guidance to industry and to practitioners with regard to specimen of choice, timing of sample collection and specifications for analytical methods and other factors [1-13]. The United States Food and Drug Administration (FDA) has also developed guidance documents intended for use by industry and FDA staff regarding the safety and effectiveness of cyclosporine, sirolimus and tacrolimus assays [14,15].
