CHALLENGES IN CYCLOSPORINE THERAPY - THE ROLE OF THERAPEUTIC MONITORING BY AREA-UNDER-THE-CURVE MONITORING

Cyclosporine has revolutionized the practice of transplantation, but its clinical application has been beclouded by a narrow therapeutic window between immunosuppressive and nephrotoxic concentrations. Marked intra-and interindividual pharmacokinetic differences preclude the use of routine dosing regimens. For example, at the intraindividual level, cyclosporine absorption improves during the first 90 days after institution of therapy. A wide range of demographic factors, namely, age, race, and concomitant drug therapy, as well as individual-specific factors produce unique pharmacokinetic behaviors in any given patient. We introduced a pharmacokinetic strategy for cyclosporine administration almost 10 years ago based on the observation that the best estimate of drug exposure was the area under the concentration-time kinetic curve (AUC) not the trough level. Early studies documented the relation between AUC and the incidence of acute rejection. Subsequent studies revealed that not only is the AUC an important predictor, but so is the consistency of drug absorption over time; namely, patients with variations >25% among AUC determinations display an increased risk of chronic rejection episodes. Therefore therapeutic drug monitoring plays an important role in the optimal care of patients under cyclosporine therapy.