Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant recipients

Elderly patients are a fast growing population among transplant recipients over the past decades. Both the innate and adaptive immune reactivity decrease with age, which is believed to contribute to the decreased incidence of acute rejection and increased infectious death rate in elderly transplant recipients. In contrast to recipient age, donor age is associated with a higher incidence of acute rejection. Pharmacokinetic studies in renal transplant recipients show that CNI troughs are > 5% higher in elderly compared to younger patients given the same dose normalized by body weight. This may impact the starting dose of tacrolimus and cyclosporine. Possibly in elderly patients the intracellular (in lymphocyte) concentrations are relatively high in relation to the whole blood concentration, resulting in a stronger pharmacodynamic effect at the same whole blood trough concentration. For cyclosporine this has been shown, but it is not clear if the same is true for other immunosuppressive drugs. Pharmacodynamic studies have compared the inhibition of target enzymes, or more downstream effects of immunosuppressive drugs, in younger and older patients. Measurement of nuclear factor of activated T-cell (NFAT)-regulated gene expression (RGE), a pharmacodynamic read-out of CNI, is a promising biomarker of immunosuppression. Low levels of NFAT RGE are associated with increased risk of infection and non-melanoma skin cancer in elderly patients. Clinical trials to evaluate the safety and efficacy of immunosuppression regimens in this specific patient population, which is underrepresented in published trials, are lacking. More studies in elderly patients are needed to investigate the impact of age on the pharmacokinetics or pharmacodynamics of immunosuppressive drugs, and to decide on the optimal regimen and target levels for elderly transplant recipients.