Comparison of several approaches of therapeutic drug monitoring of cyclosporin A based on individual pharmacokinetics

Objective: The clinical outcome of patients after organ transplantation is correlated with cyclosporin A (CyA) exposure. It is generally accepted that the area under the concentration-time curve (AUC) provides a reliable mean s for drug exposure. However, in routine therapeutic drug monitoring (TDM) of CyA, trough levels are mostly used. Currently, a number of different new concepts of CyA-TDM, including approaches such as single, double or triple time-point and abbreviated AUC determinations, have been introduced. The p urpose of this study was to compare the predictive value of the different s trategies of TDM. Methods: Calculations were based on 40 individual concentration-time profil es after oral administration of CyA to patients who had been included into an ongoing prospective clinical trial. Non-compartmental analysis was used to calculate the AUC(0-12h) Multiple linear regression was performed to des cribe the relationship between the different sets of blood concentrations a nd the respective AUC(0-12h) as well as to evaluate their predictive value regarding AUG. Predictive performance was assessed by prediction bias and p rediction precision, which were estimated as the mean prediction error and root mean squared error, respectively. Results: When comparing the various combinations of time points, it was fou nd that one-point approaches showed the strongest differences with regard t o the predictive value; the associated r(2) values differed from 0.203 to 0 .792. The two and three time-point approaches showed lower differences - r( 2) 0.802-0.972. The four-point and five-point approaches (r(2) 0.942-0.982) were the strongest predictors for CyA AUC(0-12h) Relative bias ranged from -27.7% to 63.8% and changed significantly when multiple-point predictors w ere used. In those cases, the predictive performance improved. Considering the predictive performance as well as the smallest bias and highest predict ion precision, C3, C1 + C3, C1 + C3 + C6 and C1 + C2 + C3 + C6 were the bes t predictors. Conclusion: The results of this study indicate that in kidney transplant pa tients a clinically sufficient precise estimation of the CyA AUC is possibl e using two or three concentration-time points.