Influence of interactions between immunosuppressive drugs on therapeutic drug monitoring.

With the emergence of more immunosuppressive drug combinations in transplantation, the number and complexity of drug interactions have increased and constitute a growing challenge for clinicians. Especially, clinically relevant immunosuppressive drug interactions require prompt identification, intensified monitoring of drug concentrations and adequate dosing responses. The drug interaction whereby cyclosporine, as opposed to tacrolimus, inhibits the enterohepatic (re)circulation of mycophenolic acid and its inactive MPAG metabolite, will result in significantly lower dose-corrected MPA concentrations in cyclosporine-treated patients which in turn will lead to early clinical MPA underexposure in 50% of patients receiving 2 grams of MMF per day. Also, when reducing or withdrawing cyclosporine or switching to tacrolimus as alternative calcineurin-inhibitor and vice versa, this important drug interactions needs to be taken into consideration. The combination of cyclosporine and the proliferation signal inhibitors (PSI) sirolimus and everolimus, requires dose reductions of both drugs because of a well-established synergistic drug interaction which will lead to increased nephrotoxicity when left unadjusted. Despite the observations that clinically important drug interactions between PSI and tacrolimus are apparently lacking, switching between calcineurin-inhibitors in renal recipients requires intensified monitoring of PSI concentrations. Finally, when corticosteroid doses are substantially reduced or completely withdrawn from a tacrolimus-based immunosuppressive regimen, a moderate increase of tacrolimus concentrations will ensue, albeit without any clearly described clinical consequences. More attention for clinically relevant immunosuppressive drug interactions is warranted in this era of tailor-made transplantation medicine whereby an increasing number of immunosuppressive drug combinations are, not uniquely, but rather sequentially used during the life course of a transplanted organ.