Nocturnal Monitoring: How Digital Measures and Machine Learning Reveal the Unseen Impact on Drug Safety

Nocturnal Monitoring: How Digital Measures and Machine Learning Reveal the Unseen Impact on Drug Safety?

Preclinical animal studies are crucial for assessing drug safety, providing essential data on how drug candidates interact with biological systems before entering human trials. Traditionally, these studies focus on monitoring during the animals' light cycle, which aligns with human daytime. However, this practice may overlook important physiological and behavioral responses that occur naturally during the animals' active (dark) period. Think of it like watching a sloth during the day—you’ll miss the party that happens after dark. Recent studies using continuous digital monitoring demonstrate that many critical changes, such as shifts in circadian rhythms or early signs of distress, are often only detectable during the animals' nocturnal phase. This blog explores the importance of nocturnal monitoring and its potential to reveal previously overlooked aspects of drug safety.?

The Circadian Rhythms of Lab Animals: Why Timing Matters?

Rodents, such as rats and mice, are primarily nocturnal, with peak activity occurring during the night. Metabolic processes, cardiovascular activity, and neurological functions follow this rhythm, influencing how animals respond to external stimuli, including drugs. Imagine trying to judge an owl’s energy levels based on how much it yawns at noon. It’s no wonder we miss so much with daytime-only monitoring!?

For instance, in a study on aging C57BL/6J mice, significant differences in activity and breathing rates were observed between the light and dark cycles, with older mice exhibiting lower nocturnal motion and altered circadian rhythms. These findings highlight the risk of missing key data by focusing only on the light cycle, as many behaviors and physiological changes, such as feeding, grooming, and hormonal fluctuations, occur predominantly during the night.?

Nocturnal Monitoring: A New Window into Drug Safety?

Advancements in digital monitoring technologies allow for 24-hour observation of animals, providing a complete view of their behavior and physiology without disturbing them. This continuous monitoring is particularly valuable in drug safety studies where certain adverse effects may only manifest during the animals' active (nocturnal) phase. It’s like watching a thriller movie—you wouldn’t turn it off just before the big twist, right? Similarly, nighttime is when the “plot twists” in animal behavior often occur.?

In the aging study, nocturnal breathing rates were significantly reduced in older mice, correlating with age-related declines in cardiopulmonary function. These differences, more apparent during the dark cycle, underscore the importance of nighttime monitoring for detecting early signs of drug-induced respiratory distress. Monitoring sleep patterns and circadian rhythms can also reveal early signs of drug toxicity that might be missed during standard daytime assessments.?

Case Studies: What We’re Learning from the Night?

Several studies have shown the value of nocturnal monitoring in drug safety. In the study on aging mice, continuous monitoring revealed age-dependent responses to routine procedures like cage changes and blood collection. Older mice exhibited greater fluctuations in nighttime activity and breathing rate following these stressors, suggesting increased sensitivity and reduced physiological resilience compared to younger animals.?

Picture this: while the young mice are moonwalking through the night, the older ones are already exhausted after a slow waltz. But without nocturnal monitoring, you’d never see who’s partying and who’s snoozing.?

One notable example involved the use of AI-driven home cage monitoring to assess drug-induced changes in locomotor activity. Rodents exposed to a CNS-active compound showed significant alterations in nocturnal activity, correlating with adverse events later observed in clinical trials. This demonstrates how early nocturnal monitoring could flag compounds for further scrutiny, potentially preventing costly late-stage failures.?

The Technical Challenges and How to Overcome Them?

Collecting continuous data over 24-hour periods generates vast datasets, requiring advanced tools for analysis. Integrating behavioral, physiological, and biochemical endpoints can be complex, demanding a multidisciplinary approach.?

Maintaining consistent environmental conditions is also critical. In the aging mouse study, changes in circadian rhythm metrics, such as activity onset and bout duration, were noted during the dark cycle, reinforcing the need for precise environmental control in long-term monitoring. Despite these challenges, AI-powered algorithms are making it easier to process and analyze large datasets, enabling the identification of early signs of drug toxicity in real-time.?

Implications for Drug Development and Regulatory Submissions?

The insights gained from nocturnal monitoring have significant implications for drug development. By capturing a more complete view of a drug's safety profile, companies can make more informed decisions earlier in the development process, potentially avoiding late-stage failures. Nocturnal data can also enhance the prediction of human-relevant adverse events, improving the chances of successful clinical translation.?

Regulatory agencies, including the FDA, are increasingly receptive to data generated from novel monitoring technologies, provided that it meets stringent validation and reproducibility standards. In fact, digital biomarkers, such as those continuously measured in home-cage environments, are increasingly being considered valuable tools for preclinical studies due to their non-invasive nature and ability to detect early signs of distress.?

Continuous, 24-hour monitoring may soon become a recommended component of preclinical safety assessments, particularly for CNS-active compounds or those targeting circadian-regulated pathways.?

Conclusion: Shining a Light on the Night?

Nocturnal monitoring offers a comprehensive understanding of a drug's effects by aligning study designs with the natural circadian rhythms of lab animals. Studies, such as those involving aging mice, show that continuous monitoring of nocturnal activity can reveal age-related declines in physiological resilience. By embracing nocturnal monitoring, we can uncover critical insights that improve the translational relevance of preclinical findings, ultimately leading to safer, more effective therapeutics.?

?

References ?

Digital Biomarkers Enable Automated, Longitudinal Monitoring in a Mouse Model of Aging - PubMed (nih.gov)?

Digitalization of toxicology: improving preclinical to clinical translation - PubMed (nih.gov)?

Emerging Role of Translational Digital Biomarkers Within Home Cage Monitoring Technologies in Preclinical Drug Discovery and Development - PubMed (nih.gov)?

?