PHYSIOLOGICALLY-BASED PHARMACOKINETICS OF CYCLOSPORINE-A - EXTENSION TO TISSUE DISTRIBUTION KINETICS IN RATS AND SCALE-UP TO HUMAN

The tissue distribution kinetics of i.v. Cyclosporine A (CyA) was inve stigated extensively in rats. The concentration-to-time data of 11 org ans were analyzed separately using local physiologically based pharmac okinetic models, involving nonlinear plasma-to-blood cell distribution , membrane-permeability-limited plasma-to-tissue distribution and eith er linear or nonlinear tissue binding. Two global physiologically base d pharmacokinetic models were then evaluated, each comprising arterial and venous pools together with the 11 organs, adopting either of the two local models. Both global models successfully described the blood and tissue distribution kinetics of CyA. In nonlinear model, the estim ated dissociation constants (K-d) for the intracellular saturable bind ing ranged 0.2 to 60 ng/ml among the organs, which are comparable with values reported for cyclophilin-CyA binding in vitro. The predicted h uman pharmacokinetic profile using the physiologically based pharmacok inetic models, after scale-up of physiological parameters from rat to human, generally agreed with the observations following i.v. and oral administration, with moderate discrepancies due presumably to uncharac terized Species differences and/or the effect of i.v. vehicle on the C yA binding in plasma. Nevertheless, the models allow reasonable predic tion of drug exposure at the biological target, i.e., intracellular, u nbound CyA, which may differ among various organs according to the loc al physiological elements, e.g., tissue cellular membrane permeability . As well as helping optimize the CyA regimen in patients, who are lik ely to exhibit a variety of physiological and pathological conditions, the modeling suggests possible insights into the known grafted-organ specific efficacy of CyA.