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Update on chronotherapy: it's about time

Mark Greener

Mark Greener

Mark Greener is a freelance medical writer and journalist

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First published: 16 June 2023

Abstract

Chronotherapy is a promising approach to drug dosing that optimises the timing of administration to synchronise with our circadian rhythms. This article discusses how researchers are finding ways to utilise chronotherapy's potential to increase the efficacy and safety of various drug therapies.

Our bodies dance to the music of time. Each life, unless tragically curtailed, follows Shakespeare's seven ages from the cradle to the grave. Each year, as autumn marches toward the winter solstice, we may feel blue, perhaps even experience seasonal affective disorder. Each day, we sleep, drink and eat, driven by almost irresistible circadian rhythms.

Increasingly, researchers suggest that drug dosing should reflect these 24-hour oscillations. This approach, called chronotherapy, recognises, for example, that low-dose (75–100mg) aspirin and simvastatin are “consistently more effective” when taken in the evening. Insulin glargine is more effective when given in the morning.1 In cancer patients, chronotherapy improves the efficacy and reduces the toxicity of capecitabine (a prodrug of 5-fluorouracil), oxaliplatin, doxorubicin plus cisplatin, and, probably, immune checkpoint inhibitors and cancer vaccines.2-6 The protective immune response against certain pathogens, such as hepatitis A virus and SARS-CoV-2, may depend on the time of day when the vaccine is administered.7

“Using retard formulations [which have a constant release rate] for cardiovascular disease is ‘chronotherapy’ in disguise,” says Dr Robert Dallmann, Associate Professor of Cancer Biomedicine and Chronotherapy, Warwick Medical School. “Nevertheless, chronotherapy's potential is largely untapped. Although understanding the underlying mechanisms has led to more activity in this space, clinical practice is changing only glacially.”

Not surprisingly, disrupting these fundamental rhythms can be bad for your health. Indeed, the International Agency for Research on Cancer classified night shift work as “probably carcinogenic to humans”.8 “Maintaining synchrony is key to optimal health, and this includes synchrony between our internal clocks and the external world, as well as synchrony among all the internal clocks,” a recent paper commented.9

Numerous commonly used drugs, including esomeprazole, methylphenidate and rituximab, target genes that control certain circadian rhythms.10 So, drugs could help ensure synchrony between our biological clocks and the environment. For example, the suprachiasmatic nuclei (SCN) in the hypothalamus, the body's central clock, contain phosphodiesterase (PDE) 5. In animal models, sildenafil, which inhibits PDE5, enhances circadian responses to light and reduces the time the clock needs to reset after advances of the light-dark cycle. So, sildenafil may help circadian adaptation to environmental changes, including countering eastbound jet lag.11

Keep to the beat

Biological ‘clocks’ throughout the body ensure that our circadian rhythms synchronise with each other and the Zeitgebers (cues, such as light, that regulate circadian rhythms). Light stimulates rods, cones and some retinal ganglion cells that project to the SCN (see Box 1). In turn, the SCN express circadian genes to synchronise with the light-dark cycle. Every cell in the body seems to contain a circadian oscillator (so-called peripheral clocks), which the SCN control by direct innervation, neuropeptides, hormones and body temperature.4 Light seems to be the strongest Zeitgeber. But other Zeitgebers, such as temperature, feeding, exercise and pathogens, fine-tune the rhythms. Numerous feedback loops synchronise the various clocks.4

Box 1. Chronotherapy and the blind

Intrinsically photosensitive retinal ganglion cells project to the suprachiasmatic nuclei (SCN) allowing the master clock to synchronise with the light-dark cycle.4 Rods and cones signal to the SCN through non-photosensitive retinal ganglion cells. Not surprisingly, therefore, blind people can show several sleep and circadian changes, including delayed (circadian clock moves towards the evening) and advanced (sleepiness in the evening and waking very early in the morning) sleep phase disorders. Up to half of blind patients without light perception may experience non-24-hour sleep-wake disorder (progressive delay in sleep onset).27

Dr Vasudevan adds that chronotherapy can help people with visual impairment and circadian clock disorders. “People without light perception and those with disorders of the circadian clock itself fail to entrain their internal clock to the external world, such that they are constantly drifting [called free running] across time,” he comments. “Agents that stabilise their circadian system by mimicking pathways activated by light can stabilise their rhythms and give them a sense of internal time.”

Changes in gene transcription drive many biological clocks.4, 12 A study that explored gene expression in 914 people found tightly synchronised rhythms in messenger RNA across 46 tissues. However, males and females shared only about 50% of the genes that showed rhythms. The remainder were expressed in only one sex or showed different patterns. Gene expression rhythms were more sustained in females than males and, in general, became less pronounced with age.12 “The bottom line is that about 50% of genes are rhythmic in at least one tissue. However, there is additional regulation at the protein level,” Dr Dallmann says.

Time to dose

Chronotherapy could allow drug dosing tailored to a disease's oscillating signs and symptoms. In people with asthma, for example, airways are narrowest, symptoms are often worse and the number of eosinophils peaks in the lung at about 04:00.13 “The classic example of chronotherapy is treating nocturnal asthma with delayed-release formulations of theophylline,” Dr Dallmann says. “Similarly, we should consider the timing of signs and symptoms when prescribing for arthritis and hypertension.”14-16

In healthy people, blood pressure reaches a nadir at about midnight.15 Blood pressure rises rapidly before we wake in the morning in anticipation of our rising to face the day. People without the healthy overnight blood pressure dip of 10% to 20% are, for instance, more likely to develop and die from cardiovascular disease or develop hypertensive complications, such as renal or eye disease.15 Some cardiovascular risk factors, such as hypertension, can blunt the decline, while taking antihypertensives at night can normalise nocturnal dipping.15, 16

Malignant cells can show abnormal circadian rhythms that may contribute to cancer development.6 Dr Dallmann adds that the toxicity of various cancer chemotherapeutics varies during the day depending on enzyme activity (eg capecitabine) or kidney perfusion (eg cisplatin).2, 3 Oxaliplatin, for example, is best tolerated when delivery peaks at 16:00 hours.4 When used in ovarian cancer, administering doxorubicin at 06:00 and cisplatin between 16:00–20:00 reduced complications and toxicity with both drugs and increased tumour response and five-year survival.4

In addition, adaptive immunity seems to be weaker if stimulated in the evening than during the day. So, immune checkpoint inhibitors for cancer may be more effective if infused before mid-afternoon.5 Animal studies also suggest that the efficacy of cancer vaccines may depend on the time of day.6 However, prospective clinical studies are needed.

“By optimising the timing of delivery, we may be able to lower the doses and, at the same time, increase the efficacy of several drugs and reduce side-effects,” says Dr Sridhar Vasudevan, Associate Professor, University of Oxford. “This approach has shown promise in cancer chemotherapy and is being explored in other areas.”

Nevertheless, our bodies’ rhythms change depending on age and environment, which adds another layer of complexity to dosing. “Clock properties are largely genetically determined,” Dr Dallmann says. “But clock properties are also plastic. Our behaviour – light, activity, food and medication – and other processes influence these proteins. Taking a drug ‘in the morning directly after waking’ may mean 6am for one person but 12 noon for someone else. This means that defining the biological, internal time when a drug should be taken is important.”

Circadian pharmacokinetic variations

The timing of dosing could also reflect circadian variations in pharmacokinetics. “Dose equivalence of some drugs depends on time of day, reflecting the complex interactions of timed processes in the body. For example, paracetamol's toxicity varies during the day depending on CYP450 activity and the abundance of glutathione [an antioxidant] in the liver,” Dr Dallmann says.

“Circadian variations potentially influence all aspects of pharmacokinetics – absorption, distribution, metabolism, elimination and toxicity – including gastric emptying and gut motility; renal clearance and filtration rate; liver perfusion, phase I and II metabolism; and drug transporters in the gut and blood-brain barrier [BBB]. This makes circadian pharmacokinetics a fascinating, yet complex problem. The magnitude of the effects, however, is different for different drugs. The most important rate-limiting processes have to be determined for individual drugs,” Dr Dallmann comments.

Optimising the timing of drug administration could pharmacokinetically re-invigorate some older drugs. The BBB, for example, isn’t a static wall. Circadian rhythms control transporter function across the BBB. So, endocytosis across the BBB increases during sleep. Meanwhile, sleep helps clear metabolites in the BBB.17 “The BBB shows a circadian rhythm in permeability,” Dr Vasudevan adds. “This presents an opportunity to use a range of drugs that were previously considered not suitable for brain disorders due to reduced penetration. By optimising the timing of drug administration, we may hit the ‘permeable window’.”

Moreover, jet lag and shift work can cause ‘internal desynchronisation’ – in other words, organs shift to a new phase at different speeds, which can misalign rhythms and complicate pharmacokinetics. “The changes in people on night shift, or even worse rotating shifts, may be very hard to predict. This is underexplored, as far as I am aware, even for drugs where time of day effects are widely accepted,” Dr Dallmann remarks.

Ion-ing out lithium's action

In addition to being modulated by biological time, certain drugs can shift biological clocks. “This might be an unintended side-effect, such as in cancer chemotherapeutics or with sildenafil, which may be a jet lag treatment,” says Dr Dallmann. “Patients with diabetes often display faulty glucose sensing, insulin secretion and energy utilisation,” adds Dr Vasudevan. “Given [that] these processes are under the control of the circadian clock, these hard-to-treat disorders may benefit from a chronotherapy approach to strengthen the clock and thus bolster metabolic control.”

In addition, considering a drug's effect on biological clocks may help solve some pharmacological mysteries, such as how lithium, the gold-standard treatment for bipolar disorder, works. “Lithium, being a simple ion, is promiscuous,” Dr Vasudevan explains. “Lithium enters cells using transporters and channels. This influences the cell's electrophysiological properties. In addition, lithium directly binds to, and alters the function of, several proteins, such as kinases and phosphatases. Given the involvement of these target proteins in numerous physiological processes and functions, identifying a therapeutically relevant target, if a single target even exists, has been challenging.”

Lithium, for instance, modulates circadian rhythms. “Some researchers hypothesise that lithium's effect on the clock stabilises mood by regulating genes that control neurotransmitter levels, such as dopamine,” Dr Vasudevan says. “Further exploration in this area may take us closer to understanding how and why lithium works as a mood stabiliser and, in turn, developing effective yet safer (compared with lithium) drugs.” Meanwhile, exploratory studies by Dr Vasudevan and colleagues suggest the circadian response “may serve as a biomarker for predicting which patient may or may not respond to lithium, which is currently done by trial and error.”18

As far as we know, all cells have their own circadian oscillator. So, researchers use peripheral cells, such as fibroblasts, to approximate human circadian behaviour. Dr Vasudevan and colleagues found that lithium did not change circadian rhythms in fibroblasts from people who had excessively long circadian periods (more than 26 hours). These patients were more likely than those with normal patterns to stop lithium and switch to other drugs. Conversely, lithium altered circadian rhythms in fibroblasts from people with short (less than 23 hours) and medium (about 24 hours) circadian periods. These patients tended to persist with lithium.18 Dr Vasudevan and colleagues confirmed these findings in rodent models.18

Organisms as diverse as bacteria, fungi, fish, amphibians, reptiles, insects and mammals show circadian rhythms.19 In other words, circadian clocks are highly conserved during evolution. “Pathways and mutations that alter human circadian function alter mouse circadian behaviour in a similar manner, making mice an excellent model for translational studies on the clock,” Dr Vasudevan says. “However, no single animal model replicates all aspects of bipolar disorder. We need to be careful when we model complex disorders, especially where the underlying biology is murky, such as mood-related conditions.”

Untangling causality presents another problem. “Patients with bipolar disorder show fragmented sleep and circadian rhythms. These dysfunctions are not specific to bipolar disorder. They’re seen in several psychiatric disorders,” Dr Vasudevan says. “However, disrupted sleep and frequent travel across time zones can precipitate manic episodes in predisposed subjects and reflecting this, therapies for the disorder involve regimens of stable and adequate sleep. At a mechanistic level, genes and neurotransmitters that regulate mood are influenced by the circadian network. Furthermore, sleep shares several networks and transmitters with mood regulation. Therefore, disruption in the sleep or circadian system can and will affect mood-related processes. However, the directionality, causality and relationship are not yet fully established. We need well-controlled large-scale studies specifically designed to address this question.”

Alzheimer's disease and sleep

During sleep, we flush waste products, including those implicated in Alzheimer's disease, from our brains. A meta-analysis of 27 observational studies showed that people experiencing sleep problems were 68% more likely than controls to develop cognitive impairment, Alzheimer's disease or both. The authors estimate that sleep problems may account for about 15% of Alzheimer's disease cases.20

People with Alzheimer's disease could become trapped in “a self-reinforcing feedback loop” where disrupted circadian timing accelerates disease pathogenesis, such as amyloid deposition, oxidative stress and cell death. The resulting brain damage further disrupts circadian rhythms.21

“Disturbed sleep-wake behaviour, including night-time delirium, is a major factor leading to individuals with Alzheimer's disease ending up in care homes. Therefore, stabilisation of sleep will benefit caregivers, healthcare systems and patients,” Dr Vasudevan says. “More specifically, some proteins involved in regulating circadian rhythms, such as casein kinase 1, can phosphorylate [the protein] tau, which leads to tangles and neuronal death. Research efforts are well underway to see if targeting this effect with drugs benefits patients.”

Dr Dallmann notes that the relationship between Alzheimer's disease and sleep seems to be part of a “wider phenomenon”. Changes in sleep and circadian phenotypes can emerge years before the onset of other symptoms in Huntington's and Parkinson's disease. In mouse models, normalising sleep and circadian activity patterns seem to impact positively on disease progression.22

Roadblocks

So, why is chronotherapy moving only glacially into clinical practice? Dr Dallmann highlights several roadblocks including the need for biomarkers. “How can we reliably measure ‘the clock’ in patients’ tissues, tumours and so on? We know these differ from healthy humans and that disease and some drugs may interfere with circadian patterns,” he says. Recent papers explored rhythms in parameters measured as part of routine monitoring as well as molecular rhythms in patients in intensive care units.23-26 “There is more and more data from wearable technology,” Dr Dallmann adds. “But we need more studies.”

Regulators recognise that time of day is important, which should encourage further research. “Companies have to provide 24-hour data as part of an investigational new drug application for cardiovascular drugs,” Dr Dallmann says. “The pharmaceutical industry should welcome chronotherapy because they may be able to stratify patients and reduce variability.”

Nevertheless, pharmaceutical companies will need to trial any suggestions about when to take a medication. “If a drug is to be taken ‘in the morning’ what happens if the person is an extreme late chronotype? Has jet lag? Works shifts? The industry would need to consider this and regulators would probably ask for data,” Dr Dallmann comments. “This has cost implications during development as well as potential legal exposure and possible liabilities during the market phase if things go wrong.” Dr Vasudevan suggests that patent extensions or similar incentives could encourage companies to explore chronotherapeutic applications of existing drugs.

Other roadblocks to wider use of chronotherapy include education and resourcing. “We need to educate the medical community and make circadian medicine part of the curriculum,” Dr Dallmann says. “Resourcing may be less of a concern for oral medications. But in the context of recording symptoms by GPs, or hospital treatments such as injectables, resourcing may be a concern.”

Despite our built environments, heat and light at the flick of a switch, and pervasive light pollution, we’re still behoven to our circadian rhythms. But by working with, instead of against, biological rhythms, chronotherapy could help redefine the efficacy and safety of several drugs. But will chronotherapy become a central pharmacological principle? Only time will tell.

Declaration of interests

Mark Greener is a full-time medical writer and journalist and, as such, regularly provides editorial and consultancy services to numerous pharmaceutical, biotechnology and device companies and their agencies. He has no shares or financial interests relevant to this article.