STIMULATED RESPONSE OF PERIPHERAL LYMPHOCYTES MAY DISTINGUISH CYCLOSPORINE EFFECT IN RENAL TRANSPLANT RECIPIENTS RECEIVING A CYCLOSPORINE+RAPAMYCIN REGIMEN1

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Abstract
Clinically, cyclosporine (CSA, Neoral) is titrated to concentrations, and not to pharmacological effect. Intracellular interleukin- (IL) 2 was measured in phorbol myristic acid-ionomycin-stimulated peripheral lymphocytes by flow cytometry, after isolation from 14 renal transplant recipients receiving CSA+prednisone, and double-blind rapamycin (rapamycin:placebo=4:1). The proportion (%) of CD4+IL-2+ lymphocytes corresponding to CSA levels (mean±SD ng/ml) measured preoperatively (T0=0), and on postoperative day 8, before (356±63), and 2 hr after the morning dose (Cmax=1567±669), decreased from 39±16 to 15±8 and 3±1.6, respectively. Reciprocally, unresponsive lymphocytes (%CD4+IL-2−) increased with increasing CSA levels and predicted an EC50 of 249 ng/ml (CSA concentration at which CD4+IL-2− cells increased by 50% over baseline) in an Emax pharmacodynamic model. Clinically, the pharmacological effect of CSA is quantifiable, and lies in the upper end of the predicted range. In our Neoral-treated sample population, Cmax was associated with the least variable “cyclosporine effect.” Such information could potentially individualize immunosuppression, and lead to rational dosing strategies.