Immunopharmacodynamic Studies of Cyclosporine in Patients Awaiting Renal Transplantation

The immunopharmacodynamics of cyclosporine were investigated in eight hemodialysis patients awaiting renal transplantation. cyclosporine was administered orally (10 mg/kg) and intravenously (4 mg/kg), with both administrations separated by at least one week. Plasma samples were processed at 37°C and analyzed for specific cyclosporine and its four major metabolites (AM1, AM1c, AM9, and AM4N) using high‐performance liquid chromatography. In addition, the in vitro immunosuppressive activity of these serial plasma samples was estimated as a relative percentage inhibition of third party mitogenic lymphocyte proliferation stimulated with phytohemagglutinin. The relationships between concentration and effect of cyclosporine versus time were noted. These results suggest that unchanged cyclosporine concentrations in plasma correlate with mitogen‐induced lymphocyte suppression yielding significant immunosuppressant activity of cyclosporine. Control studies with plasma from healthy volunteers spiked with cyclosporine in the concentration range of 0–10,000 ng/mL were developed. A sigmoidal Emax model was fitted to the effect versus plasma concentration data. The ratio of effect versus predicted effect were calculated for intravenous cyclosporine dosing. There was a good correlation between the observed and predicted inhibitory effect.