The importance of determining circadian parameters in pharmacological studies

In mammals, most molecular and cellular processes show circadian changes, leading to daily variations in physiology and ultimately in behaviour. Such daily variations induce a temporal coordination of processes that is essential to ensure homeostasis and health. Thus, it is of no surprise that pharmacokinetics (PK) and pharmacodynamics (PD) of many drugs are also subject to circadian variations, profoundly affecting their efficacy and tolerability. Understanding how circadian rhythms influence drug PK, PD, and toxicity might significantly improve treatment efficacy and decrease related side effects. Therefore, it is essential to take circadian variations into account and to determine circadian parameters in pharmacological studies, especially when drugs have a short half-life or target rhythmic processes. This review provides an overview of the current knowledge on circadian rhythms and their relevance to the field of pharmacology. Methodologies to evaluate circadian rhythms in vitro, in rodent models and in humans, from experimental to computational approaches, are described and discussed. Lastly, we aim at alerting the scientific, medical, and regulatory communities to the relevance of the physiological time, as a key parameter to be considered when designing pharmacological studies. This will eventually lead to more successful preclinical and clinical trials and pave the way to a more personalized treatment to the benefit of the patients.