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 p rocessed at 37 degrees C and analyzed for specific cyclosporine and it s four major metabolites (AM1, AM1c, AM9, and AM4N) using high-perform ance liquid chromatography. In addition, the in vitro immunosuppressiv e activity of these serial plasma samples was estimated as a relative percentage inhibition of third party mitogenic lymphocyte proliferatio n stimulated with phytohemagglutinin. The relationships between concen tration and effect of cyclosporine versus time were noted. These resul ts suggest that unchanged cyclosporine concentrations in plasma correl ate with mitogen-induced lymphocyte suppression yielding significant i mmunosuppressant 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 fi tted to the effect versus plasma concentration data. The ratio of effe ct versus predicted effect were calculated for intravenous cyclosporin e dosing. There was a good correlation between the observed and predic ted inhibitory effect.