Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 2

Theory and Applications of Scaling Mechanistic PK/PD from Animals to Man

William J. Jusko, Ph.D.
Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY

The three primary components that control drug responses are the pharmacokinetics, the pharmacologic interface (receptors, enzymes, targets), and the biological system (genes, signals, biochemistry, physiology). Classic experience has been that similar drug effects are expected at similar drug exposures in different species. Mixed success has been made in use of allometric scaling of pharmacokinetic parameters among species with the latest methods involving allometry augmented by selected measurements (metabolic rates, protein binding, structural features). Similarly, assessing pharmacologic drug/target interactions often serves as the basis for screening for new therapeutic agents, but is sometimes confounded by pharmacogenetic differences among species. Allometric scaling of nonspecific biological structures, functions, and biomarkers premised on turnover principles can serve to extrapolate many biological systems. Mechanistic PK/PD models can account for these components of drug responses and help anticipate underlying species differences. Examples of PK/PD scaling will include a muscle relaxant, an NSAID, and erythropoietin.

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