Pharmacodynamic Monitoring of Calcineurin Inhibition Therapy: Principles, Performance, and Perspectives

Abstract

The calcineurin inhibitors (CNIs) cyclosporin A and tacrolimus are immunosuppressive drugs used extensively in allograft recipients. These drugs show large interindividual pharmacokinetic variation and are associated with severe adverse affects, including nephrotoxicity and cardiovascular disease. In current practice, CNIs are combined with other immunosuppressive drugs such as steroids and mycophenolate mofetil. Dosage is titrated based on blood concentration measurement. For further optimization of calcineurin (CN) inhibition therapy, new monitoring strategies are required. Pharmacodynamic-monitoring strategies constitute novel approaches for optimization of CNIs therapy. This review focuses on the general aspects of immunosuppressive drug pharmacodynamic monitoring and describes the methodologies used for monitoring CN inhibition therapy. Two different types of pharmacodynamic-monitoring strategies can be distinguished: (1) enzymatic strategies, which monitor inhibition of drug-target enzyme activity, and (2) immunologic strategies, which measure cellular responsiveness after in vitro simulated immunologic responses. Enzymatic tests are drug type-specific markers in which CN activity is directly determined. Immunologic strategies measure immune responsiveness at several levels, such as mRNA transcripts (intracellular) concentrations/excretion of cytokines, expression of surface activation markers, and cell proliferation. This review also discusses analytical issues and clinical experience with these techniques. The call for new methodologies to evaluate immunosuppressive therapy has led to the development of a large variety of pharmacodynamic-monitoring strategies. The first reports of their clinical relevance are available, but further understanding of the analytical and clinical variables involved are required for the development of accurate, reproducible, and clinically relevant markers.