CYCLOSPORINE MONITORING IN PATIENTS WITH RENAL-TRANSPLANTS - 2-POINT OR 3-POINT METHODS THAT ESTIMATE AREA-UNDER-THE-CURVE ARE SUPERIOR TO TROUGH LEVELS IN PREDICTING DRUG EXPOSURE

The recent introduction of a cyclosporine microemulsion demonstrating less pharmacokinetic variability than the conventional formulation off ers the potential for accurately and precisely predicting area under t he curve (AUC) with a limited-sampling monitoring strategy. This was s tudied based on the pharmacokinetic profiles from 55 stable patients w ith renal transplants who were observed on two occasions at steady sta te on both formulations. Multiple linear regression analyses were perf ormed on a training dataset from 27 patients. in which combinations of cyclosporine concentrations drawn from 0 to 4 hours postdose were reg ressed against the full AUC over the dosing interval. Predictor regres sion equations used concentration combinations ranging from one-point (concentrations at 0, 1, 2, 3, or 4 hours) through five-points tall fi ve concentrations 0 to 4 hours). The predictive performance of these e quations was then assessed in the training group with data from a subs equent profiling occasion and in the remaining 28 patients who constit uted an independent test group. Prediction bias (mean prediction error ) and prediction precision (absolute prediction error! were quantified and compared between formulations. Correlations between predicted and actual AUC were consistently stronger fur the microemulsion, suggesti ng the possibility of more accurate and precise predictions of exposur e than from the conventional formulation. For both formulations, the o ne-point predictors rendered the lowest prediction precision, and pred ictive performance improved considerably when multiple-point predictor s were used. Significantly higher precision and lower variability were observed with the microemulsion for most predictors in the both train ing and test groups. For the microemulsion, two-point (C0 + C1 or C0 C2) and three-point (C0 + C1 + C2) predictors yielded relatively unbi ased and precise exposure predictions, inasmuch as mean absolute predi ction error was less than 10% and 5%, respectively. Hence, a two- or t hree-point method may provide a clinically important improvement over the use of trough levels in monitoring cyclosporine therapy in patient s with renal transplants.