PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING OF CYCLOSPORINE DERIVATIVES IV
1994 Volume 9 Issue supplement Pages 66-69
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1994 Volume 9 Issue supplement Pages 66-69
A pharmacokinetic analytical method is presented, which was developed in Sandoz during the preclinical evaluation of a cyclosporine derivative, SDZ IMM 125. A physiologically-based pharmacokinetic (PBPK) model established based on rat data was scaled-up to those for dog and human using 1) an allometric equation for estimating transmembrane drug exchange clearance for each organ in the larger mammals, and 2) relative activity ratios of a specific cyt.P-450 subtype among rat, dog, and human, which were measured in vitro. The resultant PBPK models for dog and human successfully predicted the blood kinetics of SDZ IMM 125 measured experimentally during preclinical and clinical pharmacokinetic studies. The technique seems to facilitate the safety assessment in humans at very early period of drug development.
