Abstract

The dramatic improvement recorded during this last decade in the field of transplantation is mainly due both to the appearance of new immunosuppressive drugs (IS)/drug combinations and to a better understanding of the tenuous equilibrium between over- and under- immunosuppression. Current trends in drug association result in a progressive lowering of the IS charge and consequently in a reduction of their blood concentrations. There is no doubt that therapeutic drug monitoring (TDM) played an important role in this progress, because these are critical dose drugs: concentrations related side effects, inter-patient pharmacokinetics variability (bioavailability, metabolism, drug interactions, genetic polymorphism, ...). Analytical methods used to monitor these drugs also experienced some significant evolution with the use of LC-MSMS in clinical practice and with a constant progress in the immunoassays performances (sensitivity, specificity, reproducibility, automation). The area under the time-concentration curve (AUC) is generally considered as the best drug exposure marker, but is not appropriate in clinical practice. Single time points (mainly C0) IS concentrations remain therefore the most frequently used marker. Blood concentrations monitoring provides some helpful information to prevent side effects, drug interactions or non-compliance. Recent studies, however, suggest that the relationship between blood levels and incidence of organ rejection is not clearly established. Optimal treatment management needs therefore some additional approaches. Four personalized approaches are currently under investigation: 1. Optimization of the prediction of IS AUC with population pharmacokinetics, limited sampling strategy or Bayesian estimates, 2. Identification of genetic polymorphisms of metabolism enzymes or transport proteins (e.g. CYP3A5, P-gp, MRP2, etc.) to reach target drug concentration earlier, 3. Determination of IS drug concentration at the site of action (e.g. within target lymphocytes), and finally 4. Identification of pharmacodynamic biomarkers (e.g. intracellular IL2 in CD8+ T-cells, etc) able to better predict IS drug efficacy (and toxicity). This last approach is of particular interest and is expected to significantly progress during the coming years.

Keywords: Transplantation, immunosuppressive drugs, theory of mind