The importance of determining circadian parameters in pharmacological studies

Abstract

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.

Analysis of the Circadian Regulation of Cancer Hallmarks by a Cross-Platform Study of Colorectal Cancer Time-Series Data Reveals an Association with Genes Involved in Huntington’s Disease

“…The downregulation of BMAL1 led to significantly lower apoptosis rates for both SW480 and SW620 cells, which is in line with the assumption of the clock acting as a tumor suppressor [70]. This circadian regulation of cellular processes impacts the time of day of drug administration (chronotherapeutics), the distribution, metabolism, and excretion of therapeutic agents, and is used to improve the efficiency of anti-cancer drugs while reducing undesired side effects [71]. The genes that were oscillating in our analysis are critical elements of pathways that are dysregulated in various types of cancer [72].…”

An Optimal Time for Treatment—Predicting Circadian Time by Machine Learning and Mathematical Modelling

“…The circadian clock thus plays a central role in maintaining tissue homeostasis, which, if disrupted, could lead to disease onset or progression. Therefore, it is relevant to consider the bidirectional interplay between the internal clock of the patient and the applied therapy regimen accurately in order to enhance patient outcome and treat diseases more effectively [ 49 ].…”

Timing in drug absorption and disposition: The past, present, and future of chronopharmacokinetics

“…in vivo PK studies are often performed in rodents, the majority of which are nocturnal and exhibit higher activity during the dark period (Gaspar et al, 2019). Animals are generally entrained to 12/12‐hr light–dark cycles, using light as a strong zeitgeber, and the studied drug is administered at predefined zeitgeber times (ZT) to different groups, in the same dose (Gaspar et al, 2019). The ZT can be defined as a standardized 24‐hr notation of the phase in an entrained circadian cycle, in which ZT 0 indicates the start of the light period and ZT 12 corresponds to the beginning of darkness (Vitaterna, Takahashi, & Turek, 2001).…”

“…It may also be referred to as hours after light onset (Sallam et al, 2015). Meanwhile, circadian studies in humans should take into consideration several factors that can influence internal time and affect treatment response, namely, chronotypes (Gaspar et al, 2019). Humans can be classified according to the time of day during which their daily routines are preferably developed, that is, first half of the day (larks or morning type), second half (owl or evening type), or intermediate (Levi & Schibler, 2007).…”

“…Humans can be classified according to the time of day during which their daily routines are preferably developed, that is, first half of the day (larks or morning type), second half (owl or evening type), or intermediate (Levi & Schibler, 2007). Determining the chronotype of a patient may be used to optimize the time of drug administration or stratify them, thereby decreasing inter‐patient differences and the variability of therapeutic response (Gaspar et al, 2019).…”