Systems pharmacology model reveals the sources of the inter- and intraspecies variability in drug efficacy

The majority of previous studies investigate the drug efficacy only in nocturnal species (e.g. mice) although humans are diurnal. Here, using diurnal monkeys, we examine the effect of a daily (circadian) clock-modulator drug and find the high variability in its effect between diurnal monkeys and nocturnal mice. To identify the source of the interspecies variability, we used the systems pharmacology model, which accurately simulates the intracellular action of the drug and thus its effect in the circadian clock. This revealed that the interspecies variability in the drug effect is due to the different sensitivity of nocturnal and diurnal animals to environment light, the natural clock-modulator. Furthermore, via a combination of the model simulation and experiment, we found the molecular biomarker to predict the drug effect, which explains the high interindividual variability in the drug response. Based on these findings, we developed a model-based precision medicine strategy to treat circadian disruption. Our works show how the mathematical model can be used to reveal an unrecognized biological variable in drug efficacy translation between nocturnal and diurnal animals and enable precision medicine.