A novel approach in clinical immunosuppression monitoring: drug lymphocyte level.

ABSTRACT

Like others, we have shown a weak correlation between drug blood levels and clinical outcome and immune response. We recently established that in contrast to blood levels, drug lymphocyte levels are strongly associated with therapeutic efficacy. The discordance between the 2 methodologies regarding clinical outcome and immune response is related mainly to the weak association between drug blood level and target-cell content. This weak association explains the intra- and interindividual variabilities of the therapeutic response. These variations are related mainly to genetic and environmental factors including age, sex, body mass index, organ function, food and subsequent drug absorption, drug interactions, and the availability of extra-target-cell binding sites. These factors seem to influence the modes of action of immunosuppressive agents including drug absorption, metabolism, elimination, transport, extra-target-cell sites, as well as target-cell receptor expression and its binding affinity and specific enzyme baseline activity. Therefore, the cellular fraction of a drug at a fixed dosage is the result of the integration of out-fluxing and in-fluxing forces that are affected by genetic and environmental factors. Any redistribution of the drug between the different binding sites will ultimately affect its bioactivity with no change to its extracellular bioavailability (which is currently determined by pharmacokinetic measurements). Compared with whole-blood or plasma-level measurements, monitoring immunosuppression therapy at the site of action appears to be not only more clinically and immunologically relevant (since it measures the free fraction of the drug at its effector site), but this method also bypasses the potentially complex extracellular factors that affect bioactivity. Since the intracellular content of a drug strongly correlates with its biological effect, monitoring immunosuppression therapy at the site of action is comparable to pharmacodynamic monitoring. It is cost effective and easy to perform in clinical practice and could be used for all immunosuppressive drugs. Since it allows maximal reduction of adverse effects through dosage reduction while maintaining an optimal level of immunosuppression, it should offer a new alternative for immunosuppressive therapy monitoring and tailoring to the individual patient.