Medicine in the Fourth Dimension

Abstract

The importance of circadian biology has rarely been considered in pre-clinical studies, and even more when translating to the bedside. Circadian biology is becoming a critical factor for improving drug efficacy and diminishing drug toxicity. Indeed, there is emerging evidence showing that some drugs are more effective at nighttime than daytime, whereas for others it is the opposite. This suggests that the biology of the target cell will determine how an organ will respond to a drug at a specific time of the day, thus modulating pharmacodynamics. Thus, it is now time that circadian factors become an integral part of translational research.

Keywords: ADME; chronotherapy; circadian biology; clock genes; drug metabolism; translation.

Figure 1.. Towards the use of chronopharmacology for precision and personalized medicine.

The current state of the art indicates that although the impact of circadian rhythms on biological outcomes is acknowledged (e.g. academia and industry are more cautious in performing experiments at similar times of the day), minimal attention is given on the powerful impact that circadian mechanisms may have on drug development. Animal and clinical work show a strong correlation between clock malfunction and disease. However, there are inherent translational challenges in drug R&D such as the use of rodents (nocturnal animals) tested at daytime, which has a large impact on physiology and thus complicates the translation to humans. Clinically, there is no emphasis put on the timing of drug administration, rather the focus is on health care logistics and patient convenience. Important caveats include the fact that drug ADME properties (Absorption, Distribution, Metabolism, and Excretion) are controlled by circadian mechanisms leading to altered bioavailability at different times of the day, and that the circadian status of the pathway targeted by the drug will also impact outcome. Thus, integrating circadian knowledge on ADME properties and the activity of the targeted pathway will lead to increased efficacy and diminished side-effects. Since the majority of FDA approved drugs have circadian targets, timing drug delivery could have a large impact on the effectiveness of target activation or inhibition. What solutions are available to achieve such medical improvements? While the use of diurnal rodents would require decades to develop optimal disease models, using the acquired knowledge in nocturnal animals would be more powerful by including shifts in the light cycle or performing experiments during the animal’s active time – depending on the read-out and the physiology tested. Implementing circadian aspects in pre-clinical research will lead to new discoveries that, once applied in clinical trials (e.g. using chronotype or circadian biomarkers), may improve the impact on human health by optimizing drug efficacy and reducing side-effects. The case of Oxaliplatin is a pioneering example that led to chronomodulated infusion, with maximized treatment efficacy and minimized adverse effects.