Evolution of the therapeutic drug monitoring of cyclosporine.

The argument for the therapeutic monitoring of cyclosporin A (TDM-CyA), to optimize efficacy and safety, has been discussed in the last 25 years and it is still debated. Although CyA has been for more than 20 years the mainstay of immunosuppression in organ transplantation, no consensus has yet been achieved on TDM-CyA. The first proposed use of CyA was at fixed doses, but this was soon abandoned, and the predose, trough C0 blood level concept was introduced as a tool for TDM-CyA; however, no correlation could ever be shown between the various proposed trough therapeutic windows and major clinical events. On the contrary, the TDM-CyA of full area-under-the-curve (AUC) 0-12 exposure, significantly correlated with acute rejection and renal toxicity. The use of Neoral demonstrated that the region of most variability in CyA pharmacokinetics and the greatest calcineurin inhibition were confined within the AUC0-4, introducing the concept of absorption profiling. A further simplification come from the demonstration that C2, the single blood concentration measurement 2 hours after Neoral administration, was a significant accurate predictor of AUC0-4. The TDM-CyA with C2 has now been clinically validated in kidney, liver, and heart transplant recipients. In the last 25 years of TDM-CyA, some concepts have become clear: inadequate CyA exposure is a key risk factor for acute rejection and may contribute to the development of chronic rejection; C0 predose monitoring does not accurately measure CyA exposure. Thus, C2 single sampling offers today an innovative, simple, and accurate alternative for the pharmacokinetic clinical monitoring of CyA.