Abstract
To establish an optimal method for determining a cyclosporin A (CyA) regimen based on physiological changes that occur during immunosuppressive therapy, the relationship between apparent CyA body clearance (CL/f) and the CyA erythrocyte-to-plasma distribution ratio (CyA-EP) was examined using clinical time courses obtained during routine monitoring. The CyA-EP, which was calculated by a multiple regression formula using routine data, was increased during renal dysfunction involving the normal recovery phase after transplantation, during nephrotoxicity, during acute tubular necrosis, and during acute renal rejection. CyA total body clearance (CLt), calculated by multiplying CL/f and converted bioavailability, fc (which is equal to 0.009×LD, where LD represents the CyA level in blood per dose ratio), showed hyperbolic decay with increasing CyA-EP (the mean CLt was defined as follows : CLt=0.937/CyA-EP), whereas fc showed exponential decay with increasing CyA-EP (the mean fc was defined as follows : fc=0.593×exp (-0.155×CyA-EP)). These findings suggest that total CyA body clearance and its bioavailability were suppressed during the renal dysfunction phase. Hence, the mean CL/f as a function of the CyA-EP was given by the following equation : CL/f=1.390×exp (0.204×CyA-EP)/CyA-EP. Since the CyA-EP reflects a patient's disease state and alterations in the CyA pharmacokinetic profile, these model formulae should provide an adequate method for determining a CyA dosage regimen for several disease states after renal transplantation.
