gaps limit the translational potential of preclinical research

on A ril 2, 2017 ht://stm .scencem agorg/ D ow nladed from Despite widespread use of pharmacological agents in mouse models of human disease, the literature lacks comprehensive pharmacokinetic profiles for such studies. Coupled with a paucity of suitable data are shortcomings in the training of experimental biologists in the application of pharmacometric principles to experimental study design. Many authors simply cite previously published studies to support the selection of a particular dose, even when the cited paper lacks drug exposure data. There is an assumption on the part of researchers that if a referenced study demonstrates a biological effect—that is, any measurable physiological or behavioral effect—in a rodent at a given dose, then that same dose will also effectively perturb disease-relevant mechanistic biology in a different study. The danger occurs when the observed therapeutic effects are not linked to drug-induced mechanistic alterations at the level of the target organ. Lack of a drug exposure–response relationship in a target organ casts doubt on mechanistic interpretations. In addition, any changes in the route of drug administration, vehicle preparation, species used (rat versus mouse versus primate), age or strain of animal, transgenic modification, time points under investigation, duration of dosing, or organ targeted for intervention (for example, brain versus a peripheral tumor) can alter the relation between dose, exposure, and measured response. In such cases, assumptions regarding the mechanistic basis for observed therapeutic effects may not hold true. Preclinical pharmacological experiments that do not measure drug concentrations in