Vol. 287, Issue 2, 457-468, November 1998

Physiologically Based Pharmacokinetics of Cyclosporine A: Extension to Tissue Distribution Kinetics in Rats and Scale-up to Human¹

Ryosei Kawai, Diane Mathew, Chiaki Tanaka and Malcolm Rowland

Drug Metabolism and Pharmacokinetics, Novartis Pharma AG (R.K.) CH-4002, Basel, Switzerland; Novartis Pharmaceuticals Corporation (C.T.) East Hanover, NJ and School of Pharmacy and Pharmaceutical Science, Manchester University (D.M., M.R.), Manchester M13 9DL, United Kingdom

The tissue distribution kinetics of i.v. Cyclosporine A (CyA) was investigated extensively in rats. The concentration-to-time data of 11 organs were analyzed separately using local physiologically based pharmacokinetic models, involving nonlinear plasma-to-blood cell distribution, membrane-permeability-limited plasma-to-tissue distribution and either linear or nonlinear tissue binding. Two global physiologically based 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 estimated dissociation constants (K_d) for the intracellular saturable binding ranged 0.2 to 60 ng/ml among the organs, which are comparable with values reported for cyclophilin-CyA binding in vitro. The predicted human pharmacokinetic profile using the physiologically based pharmacokinetic 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 uncharacterized species differences and/or the effect of i.v. vehicle on the CyA binding in plasma. Nevertheless, the models allow reasonable prediction of drug exposure at the biological target, i.e., intracellular, unbound CyA, which may differ among various organs according to the local physiological elements, e.g., tissue cellular membrane permeability. As well as helping optimize the CyA regimen in patients, who are likely to exhibit a variety of physiological and pathological conditions, the modeling suggests possible insights into the known grafted-organ specific efficacy of CyA.