Emerging research shows that time-of-day dependent drug delivery may impact individuals differently based on their chronobiome
Recent research into the human chronobiome has shown that the "normal" circadian rhythm can vary significantly in healthy individuals. This means that chronotherapies which are based on an average individual's circadian rhythm may not be as efficacious for everyone.
While circadian rhythm is a long-standing term generally understood as the internal process that regulates a person's sleep-wake cycle, the concept of the chronobiome is relatively new, the term used for the first time in 2017 following landmark research at the University of Pennsylvania Perelman School of Medicine.
What is important for hospital and health system administrators to know now is that chronobiome has emerged as an individual characteristic (and potentially important consideration) for precision medicine initiatives.
Connecting Daily Variability in Molecular Networks to Treatment Effects and Ultimately Outcome?
Carsten Skarke, MD, studies the role of the human chronobiome and the possibilities of chronotherapy in health condition and disease management. Skarke works in Translational Medicine and Therapeutics at the University of Pennsylvania. (Photo source: Perelman School of Medicine, University of Pennsylvania)
Of interest is a recent interview with chronobiome research pioneer Carsten Skarke, MD, the McNeil Fellow in Translational Medicine and Therapeutics at the University of Pennsylvania. Skarke studies the human chronobiome under basal and perturbed conditions integrating multiomics, clinical and remote sensing outputs. According to Skarke, these reference data are necessary to interrogate time dependence in the incidence or severity of disease phenotypes.
Skarke suggests that a possible application of precision medicine may include targeting chronotherapy toward certain individuals-based on their chronobiome.
"If you look at the literature, you will find many cases where it is argued that disruption of circadian clocks or biorhythm is contributing to the development of a particular disease," stated Skarke, who points to ongoing research into the impact of chronic shift work.
Bringing the potential benefits of the chronobiome and chronotherapy within closer grasp are insights now gained through the new prevalence of wearable technologies.
"We are also in wonderful times right now because of all the wearables and the technology we use to analyze physiology is so scalable," Skarke told Technology Networks during an interview published in January. "Take single-cell transcriptomics for example, we can hone extremely deep into the molecular underpinnings of cells but can also analyze cells at an unprecedented scale. One vision is to use what I call 'easily collectible' data. Now we all have smartphones, which are essentially mini-computers, and we can get an awful lot of valuable information from these phones coupled to wearables like accelerometers or electrocardiogram monitors. This establishes a framework where we need to do little in order to generate data."
The question posed by Skarke? "What is the minimum set of longitudinal assessments in a patient to give certain answers we need for individualizing a therapeutic approach?"
Chronobiome, Chronobiology, Chronotherapy, and Chronopharmacology
The chronobiome concept involves how individuals respond differently to time-of-day dependent biological functions. Chronobiome expands on the idea of the circadian rhythm, which is the biological clock that controls how the body functions depending on the time of day. Many hormone levels, metabolic changes, and other biological functions fluctuate throughout the day and are controlled by a person's circadian rhythm.
Chronotherapy, sometimes called chronomedicine, is the term used to describe treatment that takes the natural circadian rhythm into consideration.
"When you give a medication, you always know the dose," Francis Lévi, MD, PhD, of Warwick Medical School in Coventry, United Kingdom, told Nature in 2018. At the time, Lévi (an oncologist and basic chronobiologist) led a team associated with INSERM, the French national biomedical research agency. "We have found that the timing is sometimes more important than the dose," stated Lévi, who is scheduled to address the World Health Summit in October 2021 and who champions personalizing cancer chronotherapy through systems medicine.
Research into Chronotherapy
While the shift toward precision medicine has been most evident in oncology, where specific chemotherapeutic treatments are more efficacious for specific patients based on their genetic profiles, researchers also are beginning to use precision medicine to understand how medications or treatments that are typically applied across the board will affect specific individuals based on their unique genetic makeup, metabolism, and other individual characteristics. Some examples include:
- Cardiac and vascular disease care: A new article to be published April 2021 in Current Opinion in Pharmacology suggests that scheduling medications according to chronotherapy can improve treatment effects. For example, before dinner/bedtime, ingestion of cholesterol-lowering medications and acetylsalicylic acid, respectively, exerts enhanced control of hypercholesterolemia and after-awakening peak of platelet aggregation. Also, bedtime ingestion of conventional hypertension medications optimizes normalization of sleep-time blood pressure (BP)-strongest independent BP marker of cardiovascular disease (CVD) risk-and most effectively prevents (chronoprevention) CVD morbidity and mortality.
- Drug-resistant epilepsy (DRE): The potential role of chronobiology in epilepsy was proposed as a basis for the development of chronotherapy-based modalities, which may have some benefit in DRE. What may prove useful, as noted in an August 2020 article in Seizure: European Journal of Epilepsy, is a personalized-based machine learning closed loop algorithm built on epilepsy-related signatures, autonomic signals, and chronotherapy. The goal is to improve response to anti-seizure drugs.
- Adrenal disorders: Recent data have demonstrated the circadian expression of clock genes in the adrenal gland, not only in cortisol-secreting adenomas, but also in aldosterone-producing adenomas and adrenocortical carcinomas. Noted in an August 2020 article published in the Journal of Endocrinology, this is among aspects of the emerging role of chrono-pharmacology in hypothalamic-pituitary-adrenal (HPA) axis disorders, the authors wrote. The issue is the impact of glucocorticoids levels at certain times of day or night, the conclusion that greater attention should be paid to the medical treatment used to correct glucocorticoid levels. That is, administering medications at an appropriate time that takes account of their pharmacokinetics, to avoid exposure to glucocorticoids late in the evening and at night.
When the effects of chronotherapy are combined with an understanding of an individual's chronobiome, it allows for a unique new application of precision medicine, which is getting better positioned to upend traditional healthcare treatment models.
Hospital administrators that are staying up to date with the cutting-edge advantages of precision medicine should pay close attention to the emerging research that is developing around chronotherapy and the chronobiomes. These two concepts are a complex, but important, example of how the future applications of precision medicine may be used to individualize advanced treatments and promote the overall health of everyone by focusing on the individual.