EFFICACY OF AREA-UNDER-THE-CURVE CYCLOSPORINE MONITORING IN RENAL-TRANSPLANTATION

Previous studies suggest that area-under-the-curve (AUC) pharmacokinet ic monitoring is superior to trough level monitoring for proper cyclos porin A (CSA) dosing, but AUC monitoring is expensive and unwieldy. Th e utility of a simplified AUC monitoring method was evaluated for pred icting AUC on the basis of three timed levels. CSA pharmacokinetic pro files were studied in 27 renal transplant patients at steady state ear ly (days), late (months), and in some patients, serially posttransplan tation. Whole-blood RIA levels were obtained at 2, 4, 6, 10, 12, 14, a nd 24 h after a once-daily CSA dose. The 6- and 24-h levels were the b est single-level predictors of AUC (r = 0.77 and 0.76, respectively). The best model predictive of AUC curves used three time points at 2, 6 , and 24 h postdose: AUC predicted = 8.6 x (24 h) + 1.4 x (2 h) + 6.2 x (6 h) + 1.57 mg x h/L; r2 = 0.986, P = 0.00001. The greatest pharmac okinetic variability occurred between 0 and 10 h postdose (absorption and distribution) between patients and even within individual patients monitored serially over time. The 12- to 24-h postdose portion (elimi nation) of the curve was consistently flat and uniform among patients. AUC were not consistent in individual patients over time. An AUC of m ore than 13 mg x h/L correlated with nephrotoxicity, whereas a value o f 8 mg x h/L correlated with protection from rejection in first-transp lant recipients. This AUC, however, was not able- to prevent rejection in reengrafted or highly sensitized patients.