Pharmacological surrogates of allograft outcome

Because virtually all of the currently available oral immunosuppressive agents show significant inter- and/or intrapatient variability, drug doses do not predict patient exposure, which is the critical parameter of efficacy versus toxicity. Therefore, at least for the critical-dose baseline immunosuppressive agents CsA and tacrolimus, all transplant centers use some sort of therapeutic drug monitoring. However, for CsA, Cminss values show a poor correlation with exposure and therefore are of limited use. Reliable therapeutic drug monitoring demands some measure of CsA absorption profiles with or without an estimate of clearance rates. The suggested methods include full AUC, limited sampling AUC, and a single 2- or 3-hour post-dose blood concentration. For tacrolimus, Cminss displays a reasonable correlation with systemic drug exposure as measured by AUC, however, there is little correlation between Cminss and clinical events within recommended therapeutic ranges. Sirolimus, which has been recently approved for use in kidney transplant recipients by the Food and Drug Administration in 2 or 5 mg doses, also shows the behavior of a critical-dose drug and that therapeutic monitoring using trough levels correlate strongly with drug exposure and the occurrence of adverse events. However, there is no approved automated assay and thus LC estimates must be utilized to estimate exposure. Pharmacodynamic drug monitoring opportunities are available for calcineurin inhibitors, MMF and sirolimus, but none is currently available for clinical use; however, the field of transplant pharmacodynamics is progressing rapidly. In the coming decade it is likely that an array of pharmacodynamic tools will be developed to complement the available pharmacokinetic information and lead to the development of models that predict optimal concentrations at the target sites in order to maximize immunosuppression and minimize toxic effects.