Therapeutic drug monitoring of cyclosporine and area under the curve prediction using a single time point strategy: appraisal using peak concentration data

Abstract

There is an ongoing debate on the use of a single concentration time point C2 for therapeutic drug monitoring (TDM) and exposure prediction for cyclosporine. The objective of the present work was to evaluate the relationship between the peak concentration (Cmax ) versus area under the curve (AUC) for cyclosporine. Using published data from renal transplant patients from an 8-12 week study with two formulations, a simple linear regression model represented by AUC - cyclosporine = Cmax - Cyclosporine × 3.9965 + 384.5 (r = 0.9647; p < 0.001) was developed. Using the regression equation, predictions of AUC from the reported Cmax data were performed; the fold difference between observed vs predicted AUC was computed and the root mean square error for the prediction was calculated. While all but one of the predicted AUCs were contained within a 0.5-2-fold difference (99.1%), a greater proportion of the AUC values were predicted within a narrower range of 0.75 to 1.5-fold difference (78.2%), suggesting the utility of Cmax as the right surrogate for predicting the AUC for cyclosporine with a correlation coefficient of 0.8698 (n = 126; p < 0.001) and a RMSE of 26.2%. Since the time to Cmax generally varies from 1 to 2 h, although the results validate the use of C2, there may be an opportunity to explore the suitability of C1 or C1.5 in a prospective study for the purpose of TDM and AUC prediction of cyclosporine.

Keywords: AUC; TDM; cyclosporine; exposure; limited sampling strategy; peak concentration; pharmacokinetics; renal; transplant.