Pharmacokinetic principles of immunosuppressive drugs

The combination of synergistic drugs is the main strategy to prevent early acute rejection and to provide long-term effective rejection prophylaxis. Evaluation of drug concentrations to guide drug dosing is routinely established for calcineurin-inhibitors CNIs and mTOR inhibitors. Arguments in favour of therapeutic drug-monitoring TDM are the large inter-patient variability of many immunosuppressants with their potential for severe toxicity and drug-to-drug interactions. The manuscript discusses several confounding factors, which influence the appropriate therapeutic window. These include decreasing risk of rejection over time, cumulative risk for toxicity with time, and the synergistic potential of combination immunosuppressive therapy with respect to efficacy and shared toxicities. In addition, a long list of donor and recipient characteristics have a direct or indirect effect on the therapeutic window, but have not been evaluated in rigorous, prospective trials. Unfortunately, only a very small number of adequately powered, prospective randomized trials evaluate different therapeutic windows for immunosuppressants or even the utility of TDM at all. Other problems of TDM include the inherent variability of absorption and drug levels and a suboptimal correlation between pharmacokinetic surrogate parameters and drug exposure for most drugs. Drugs with a high intra-patient day-to-day variability may be less suited for TDM compared to drugs with a high inter-patient, but low intra-patient variability. Furthermore it is not known whether the same parameter is suitable for controlling efficacy as well toxicity. With cumulative overexposure the effect of time might be more far more important than a specific level at a given time point and provides another fundamental dimension. A new approach of TDM, classified as pharmacodynamic (PD) drug monitoring, which directly reflects the drug's biological effects has been proposed to better assess the individual state of immunosuppression, however difficult test systems and lack of prospective trials limit this approach currently. Future studies have to take these considerations into account in order to better guide immunosuppression towards a more individualized therapy, which remains an important goal in transplant medicine.