PHYSIOLOGICALLY-BASED PHARMACOKINETIC STUDY ON A CYCLOSPORINE DERIVATIVE, SDZ IMM-125

The immunosuppressant. SDZ IMM 125 (IMM), is a derivative of cyclospor in A (CyA). The disposition kinetics of IMM in plasma, blood cells, an d various tissues of the rat was characterized by a physiologically ba sed pharmacokinetic (PBPK) model, the model was then applied to predic t the disposition kinetics in dog and human. Accumulation of IMM in bl ood cell is high (equilibrium blood cell/plasma ratio = 8), although t he kinetics of drug transference between plasma and blood cell is mode rately slow, taking approximately 10 min to reach equilibrium, implyin g a membrane-limited distribution into blood cells. A local PBPK model , assuming blood-flow limited distribution and tissue/blood partition coefficient (K-p) data, failed to adequately describe the observed kin etics of distribution, which were slower than predicted. A membrane tr ansport limitation is therefore needed to model dynamic tissue distrib ution data. Moreover, a slowly interacting intracellular pool was also necessary to adequately describe the kinetics of distribution in some organs. Three elimination pathways (metabolism, biliary secretion, an d glomerular filtration) of IMM were assessed at steady state in vivo and characterized independently by the corresponding clearance terms. A whole-body PBPK model was developed according to these findings, whi ch described closely the IMM concentration-time profiles in arterial b lood as well as 14 organs/tissues of the vat after intravenous adminis tration. The model was then scaled up to larger mammals by modifying p hysiological parameters, tissue distribution and elimination clearance s, in vivo enzymatic activity was considered in the scale-up of metabo lic clearance. The simulations agreed well with the experimental measu rements in dog and human, despite the large interspecies difference in the metabolic clearance, which does not follow the usual allometric r elationship. In addition, the nonlinear increase in maximum blood conc entration and AUC with increasing dose, observed in healthy volunteers after intravenous administration, was accommodated quantitatively by incorporating the known saturation of specific binding of IMM to blood cells. Overall, the PBPK model provides a promising tool to quantitat ively link preclinical and clinical data.