Pharmacodynamic Approach to Immunosuppressive Therapies Using Calcineurin Inhibitors and Mycophenolate Mofetil

Background: Graft survival depends on adequate immunosuppression. To evaluate the effect on the immune system of immunosuppressive therapies using calcineurin inhibitors (CNIs), several pharmacodynamic indices have been proposed to complement pharmacokinetic data. In this preliminary study we compared some of these parameters during combined immunosuppressant therapies. Methods: We treated 65 stable renal transplant recipients with cyclosporin A (CsA; n = 16), tacrolimus (TRL; n = 10); CsA + mycophenolate mofetil (MMF; n = 14); TRL + MMF (n = 13), and MMF (n = 12). Twelve nontreated healthy controls were also included. Calcineurin activity (CNA) in peripheral blood mononuclear cells was measured using 32P-labeled peptide. Interleukin-2 (IL-2) and interferon-γ production in phytohemagglutinin-activated whole blood were measured at 0 and 2 h postdose. The areas under the curves, c min, c max, and concentration at 2 h ( c 2 h) were also measured. Results: We found no differences in CNA between groups receiving CNIs alone or combined with MMF [median (25th–75th percentiles)]: CsA2 h, 3.87 (3.00–6.85)% alkaline phosphatase (AP); CsA+MMF2 h, 3.90 (1.78–5.19)% AP; TRL2 h, 5.68 (3.02–16.00)% AP; TRL+MMF2 h, 11.80 (4.05–14.63)% AP. In vitro IL-2 production was significantly lower in the groups receiving combined therapy than in groups receiving CNIs alone [median (25th–75th percentiles)]: CsA2 h, 276.52 (190.41–385.25) ng/L; CsA+MMF2 h, 166.48 (81.06–377.01) ng/L ( P <0.001); TRL2 h, 249.34 (127.48–363.50) ng/L; TRL+ MMF2 h, 122.13 (51.02–180.00) ng/L ( P <0.001). The correlations ( r ) between c 2 h and CNA 2 h postdose were as follows: CsA, r = −0.74; CsA+MMF, r = −0.84; TRL, r = −0.70; TRL+ MMF, r = −0.70 ( P <0.001 in all cases). Conclusions: The measurement of CNA may be of help in following the effect on the immune system of CNI treatments, even in combined therapies, but does not reflect the additional effect of MMF. In contrast, IL-2 in vitro production reflects the effect of both MMF and CNIs.