Since the timing and intensity of effects on a given target depend on the concentration time course of candidate drug (parent molecule or metabolites) at that target site, "in vivo" tissue and organ sensitivities can be completely different or even inverse of those observed on cells cultured and exposed "in vitro". That indicates that extrapolating effects observed "in vitro" needs a quantitative model of "in vivo" PK. Physiologically based PK (PBPK) models are generally accepted to be central to the extrapolations.