ON THE INTRAINDIVIDUAL VARIABILITY AND CHRONOBIOLOGY OF CYCLOSPORINE PHARMACOKINETICS IN RENAL-TRANSPLANTATION

The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period. The absolute percentage intraindividual difference in daytime AUC (0-12 h) ranged from 2 % to 54 % (mean 30%), and the corresponding variability in nighttime AUC (0-12 h) ranged from 5 % to 80 % (mean 34 %). The pharmacokinetic variables t1/2, t(max) and C(max) were more variable than the AUC (0-12 h) both during the day and at night. The evening trough level was significantly lower than the morning trough level; 185 ng.ml-1 versus 223 ng.ml-1. This, together with a significantly longer t1/2 in the night than the day, suggested circadian variability in the pharmacokinetics of CsA. In a separate retrospective study in 162 renal transplant recipients given CsA by constant intravenous infusion, repeated CsA blood concentration measurements at steady state showed lower concentrations during the day than the night, suggesting higher CsA clearance during daytime. It is concluded that CsA pharmacokinetics in renal transplant recipients, besides the well-known interindividual variability, also displays large intraindividual variability as well as circadian variation. Our findings further emphasize the necessity and difficulty of pharmacological monitoring in the clinical use of CsA in organ transplantation.