Chronotherapy: an innovative approach to maximize drug efficacy, reduce side effects, and improve patient outcomes through aligning with the body’s circadian

Authors

Abstract

Our aim in this review is to provide an inclusive overview of the scientific principles, clinical applications, challenges, and prospects of chronotherapy. Circadian rhythms are an internal timing system that governs almost all physiological functions in the human body. Circadian rhythms influence health and illness in a variety of ways, including hormone secretion, blood pressure regulation, drug metabolism, and sleep-wake cycles. The practice of coordinating medical care with these innate biological cycles, or chronotherapy, has become a cutting-edge strategy to increase medication effectiveness, minimize adverse effects, and enhance patient outcomes. The science underlying chronotherapy and its use in a variety of therapeutic domains, including cancer, cardiovascular disease, diabetes, asthma, neurological disorders, and psychiatric conditions, is examined in this review article. We also look at the fundamental molecular clock mechanisms, how they affect pharmacokinetics and pharmacodynamics, the difficulties in clinical practice, and the potential of this individualized treatment approach in the future. By moving away from “one-size-fits-all” dosing and toward customized, rhythm-based care, the evidence suggests that chronotherapy has the potential to completely transform contemporary medicine.

Keywords

Introduction

Modern medicine has long been guided by fixed dosing schedules: “Take one tablet in the morning and one at night.” While convenient, this approach often overlooks the body’s biological rhythms [1]. Human body organs’ physiology is changing throughout the day; those oscillations are controlled by internal clocks called circadian rhythms [2]. The suprachiasmatic nucleus (SCN) is the primary circadian pacemaker in mammals that affects the different physiological functions, including those relevant to drug administration and response [3, 4]. In response to these variations, chronotherapy emerged as a paradigm shift, and it is a therapeutic strategy that optimizes drug administration to be aligned with the body’s circadian rhythms, thereby enhancing drug efficacy, reducing adverse drug reactions, and improving patient adherence [5].
Circadian rhythms coordinate diverse processes such as body temperature, hormone secretion, digestion, cardiovascular activity, and immune responses [6]. Disruption of these rhythms due to factors such as shift work, artificial light at night, irregular sleep–wake cycles, or mistimed eating has been increasingly recognized as an independent risk factor for different diseases, with a growing body of evidence links circadian misalignment to key pathophysiological mechanisms, including endothelial dysfunction, oxidative stress, inflammation, and autonomic imbalance [7]. Consequently, linking the disruption of circadian rhythms to the onset and progression of numerous diseases, this emphasizes the crucial role of these biological rhythms in health promotion and improving treatment outcomes [8]. Therefore, the inter-correlation between physiological functions and circadian regulations formulates the fundamental ground for chronotherapy, aiming to use those dynamics for pharmacotherapy optimization [9]. The understanding that biological functions, including drug metabolism and cellular responsiveness, exhibit significant circadian variation has led to the emergence of chronopharmacology, which investigates the temporal aspects of drug action [10]. This field acknowledges that a drug’s efficacy and toxicity depend merely upon time of administration, because the pharmacokinetics parameters, such as absorption, distribution, metabolism, and excretion significantly affected by circadian fluctuations [8, 11]. For example, the same drug has different effects when taken in the morning or evening, the observation which led to the rise of chronotherapy [12].
Chronotherapy is the art of using the existing drugs more sensibly, but not to invent and prescribe new ones, studies found that some antihypertensive medications has the potentials of lowering morning surrogates more effectively when taken at night time, adverse drug reactions of cancer chemotherapy exhibit reduction when used at specific times of day, and using anti-asthmatic medications at evening control the symptoms that often worsen at night [5, 12, 13].
Our aim in this review is to provide an inclusive overview of the scientific principles, clinical applications, challenges, and prospects of chronotherapy.
Biological Basis of Chronotherapy
The Circadian System
The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels [14]. A master pacemaker located in the suprachiasmatic nucleus (SCN) synchronizes peripheral tissue clocks and extra- SCN oscillators in the brain with each other and with external time. Different time cues (so-called Zeitgebers) such as light, food intake, activity, and hormonal signals reset the clock system through the SCN or by direct action at the tissue clock level [15]. Peripheral clocks exist in nearly every organ, from the liver to the heart, lungs, and kidneys [16]. These peripheral clocks, while influenced by the central pacemaker, also possess autonomous oscillatory capabilities, allowing for tissue-specific regulation of physiological processes [17]. At the molecular level, circadian clocks are based on a system of transcriptional/translational feedback loops oscillating with a period of about 24h [18]. In mammals, the CLOCK/BMAL1 transcriptional activator complex regulates a set of central clock genes like mPer1, mPer2, mCry1, and mCry2 [19]. These genes regulate cycles of transcription and translation, generating 24-hour oscillations. This molecular machinery influences gene expression related to metabolism, hormone release, enzyme activity, and cell division [18].
Relevance to Drug Action
Pharmacokinetics is defined as how the body affects drugs through the stages of absorption, distribution, metabolism, and excretion of drugs (ADME). Each of these is affected by circadian rhythms [20].
Absorption
The fluctuation of gastrointestinal motility, activity of enzymes and pH throughout the day considerably are of main factors that affects the absorption of the drugs, instantly the drug is said to be bioavailable when it reach the systemic circulation, many factors affect the bioavailability of a drug, one of them is the time of drug administration, the impacts on drug bioavailability stressing the need for chronotherapy consideration [12, 21, 22].
Distribution
Plasma protein Bindings and blood flow are among many factors affecting the distribution of a drug to different body tissues, and they vary circadianly [10]. This circadian modulation of distribution can alter drug concentrations at target sites, thereby leading to pharmacodynamic drug alterations.
Metabolism
Activity of liver enzymes, particularly that of cytochrome P450 isoforms, is the cornerstone of a drug’s biotransformation, exhibiting significant diurnal oscillations [23]. Such rhythmic fluctuations in P450 activity constitute a cornerstone of hepatic drug metabolism, profoundly shaping therapeutic efficacy and toxicity [21]. Indeed, the timing of drug administration can markedly alter hepatic metabolism because circadian-driven fluctuations in P450 expression and activity affect absorption, distribution, metabolism, and excretion processes [24].
Elimination
Circadian rhythm is clearly noticed in the renal functions, where the blood flow to the kidneys, glomerular filtration rate, and rates of tubular secretion affect the elimination of the drugs and their metabolites [17, 25]. The circadian variability in the pharmacokinetics parameters in the light of drug elimination emphasizes the rational need for chronotherapy, showing that the drug dosing and dosing intervals are not static variables, yet they depend crucially on the body’s biological clock, thereby the treatment outcomes can be optimized through enhancing efficacy and reducing adverse drug reactions [26, 27, 28]. Furthermore, the circadian clock also influences cellular processes essential for the action of drugs, such as cell cycle regulation, DNA repair mechanisms, and immune responses, thereby modulating the pharmacodynamics effects of various therapeutic agents, therefore the complex interaction between pharmacokinetics, pharmacodynamics, and the circadian system offering a fundamental understanding for optimizing drug administration timings in diverse therapeutic contexts [29, 30]. Therefore, a detailed understanding of the chronobiological regulation of drug disposition and cellular responsiveness is essential for developing effective chronotherapeutic strategies [2, 31, 32].
Chronotherapy in Different Diseases
Cardiovascular Diseases
A strong circadian rhythm has a strong association with cardiovascular events. The incidence of various cardiovascular diseases, including acute myocardial infarction and arrhythmia, exhibits diurnal variation, underscoring the importance of understanding the influence of the body’s internal clock on cardiovascular functions [33]. For example, the occurrence of ischemic heart disease, including myocardial ischemia, angina pectoris, acute myocardial infarction, and sudden cardiac death, is disproportionately higher during the initial hours of daily activity and in the late afternoon or early evening [34]. Early morning is associated with high rates of strokes and heart attacks, which is the time of peaks of blood pressure, platelet aggregation, and sympathetic activity [12]. Consequently, by targeting those high-risk periods, the treatment outcome of antihypertensive, antiplatelet, and anti-hyperlipidemic drugs can be improved significantly [12]. For instance, administering certain antihypertensives at night can more effectively control the nocturnal blood pressure dip and subsequent morning surge, which are critical in preventing adverse cardiovascular events [35]. Therefore, the approach of aligning the drug effects with natural circadian rhythms of cardiovascular risk can protect effectively against myocardial infarction and stroke [35]. Similarly, because of the peaks of cholesterol synthesis occurring nocturnally, HMG-CoA reductase inhibitors (statins) are prescribed for evening administration, which maximizes their therapeutic benefit. Moreover, chronotherapy in cardiovascular diseases extends to conditions like congestive heart failure and arrhythmia, where symptom exacerbation and physiological vulnerabilities often exhibit predictable daily patterns, thus benefiting from timed interventions [36].
Cancer
One of the most studied areas of chronotherapy is the field of oncology. While the DNA repair and cell division follow circadian rhythms, the administration timing of oncology medication can maximize tumor killing and spare the healthy cells, using the differential circadian sensitivities between rapidly dividing cancer cells and normal quiescent cells, thereby improving the therapeutic index of cytotoxic agents [37, 38]. For example, gastrointestinal adverse drug reactions and bone marrow toxicity due to oxaliplatin and 5-fluorouracil show reduction when administered according to circadian schedules [39]. This strategic timing enhances treatment tolerability and can lead to improved patient outcomes by reducing severe side effects associated with conventional chemotherapy regimens [40]. Clinical trials stated a significant association between tolerability and improved survival rates when chemotherapy is administered according to the circadian cycle [41].
Asthma and Respiratory Disorders
The symptoms and signs of asthma (coughing, wheezing, airway narrowing) worsening at night and early morning, this situation is directly associated with the circadian declines in lung function and cortisol levels, to encounter the nocturnal airway inflammation and bronchoconstriction, it is highly appreciated to administer corticosteroids and bronchodilators at evening, studies found that inhaled corticosteroids and bronchodilators are more effective when administered in the late afternoon or evening, the approach of time targeting enhance overall asthma control, reduce nocturnal awakenings, and improve patient’s quality of life [1, 8, 13, 42].
Diabetes and Metabolic Disorders
The beta-cell of the pancreas, insulin sensitivity, and glucose tolerance all fluctuate during the day, and it is found that the body’s handling of carbohydrates is more better in the morning time than at evening [43], studies mention that administering oral hypoglycemic medications in treatment of type-2 diabetes are more effective during the periods of higher resistance [44]. Time-targeted strategies, which aim to synchronize external cues with the molecular clock to improve metabolic outcomes, have positive effects on metabolism in humans, with several studies showing that time-targeted feeding improves body weight loss and glucose tolerance [45].
Neurological Disorders
Neurological and neurodegenerative diseases such as epilepsy, Parkinson’s disease, and Alzheimer’s disease are strongly associated with circadian disruption [46].
Epilepsy: studies found that seizures are clearly governed by circadian rhythm; therefore, seizure control is achieved using chronotherapy [47]. Improving antiepileptic efficacy and reducing their adverse drug reactions were highly associated with the timing of administration of the drugs to the patient’s individual seizure susceptibility rhythms.
Parkinson’s Disease: Motor symptoms, such as tremors and rigidity, and non-motor symptoms, like sleep disturbances, often exhibit diurnal fluctuations, suggesting potential benefits from timed dopaminergic therapies [48].
Alzheimer’s Disease
Circadian rhythm dysfunction is a fundamental factor in aggravating Alzheimer’s Disease (AD), crucially contributing to the declining cognitive and, as well as cognitive enhancer, which endow a promising therapeutic chance [49].
Although there is still interest in symptomatic agents that address sleep and circadian processes, according to clinical development pipelines, there are currently few late-stage cognitive enhancers that specifically target circadian biology [50, 51].
Psychiatric Disorders
Circadian rhythm disruption is closely associated with bipolar disorder, depression, and mood disorders [22]. As a result, chronotherapeutic strategies, like light therapy or timed antidepressant administration, may greatly stabilize mood and enhance sleep patterns in afflicted people [52]. By taking advantage of the knowledge that neurotransmitter synthesis and receptor sensitivity are also influenced by circadian rhythms, this strategy allows for more accurate pharmacological intervention targeting increased therapeutic benefit [12]. This thorough comprehension emphasizes how important it is to take circadian biology into account when developing and administering drugs in a variety of clinical settings. The fields of pharmaceutics have expanded due to the growing interest in chronopharmacology, and many more sub-disciplines are anticipated to coexist soon [53]. By releasing therapeutic agents at precise times to correspond with patient circadian rhythms and disease chronopharmacology, the development of chronotherapeutics—in particular, pulsatile drug delivery systems—represents a substantial advancement in optimizing drug efficacy [54]. This novel strategy maximizes therapeutic results while reducing adverse effects by ensuring that the drug’s maximum effect occurs during the time of greatest symptomatic manifestation or physiological vulnerability [37]. Targeted drug release is made possible by this technique, which is essential for diseases like cardiovascular and inflammatory disorders that show significant diurnal variations in their pathophysiology.
Immunology and Infections
Strong circadian regulation is present in the immune system; different day hours have an impact on infection susceptibility, inflammation, and vaccine responses [55]. Given the circadian rhythmicity of immune function, the timing of immunomodulatory treatments or antimicrobial agents may have a substantial impact on their effectiveness and minimize adverse drug reactions [56]. Some studies stated that vaccinations administered in the morning elicit stronger antibody responses than those administered in the afternoon, [22]. This phenomenon is explained by the fact that antigen- presenting cells and T-helper cells are most active in the early hours of the day, which results in a stronger adaptive immune response [57]. For medications with limited therapeutic indices, where exact temporal control can greatly enhance safety and efficacy profiles, this optimization approach is especially pertinent [37]. This exact temporal control has been made possible by the development of chrono-modulated drug delivery systems, which include technologies such as Diffucaps, osmotic release oral system (OROS), and 3D printing, which allows for drug release profiles that are customized to particular circadian patterns [48].
Pharmacokinetics and Pharmacodynamics in Chronotherapy
Understanding how drug timing affects pharmacokinetics (PK) and pharmacodynamics (PD) is essential for chronotherapy.
Pharmacokinetics
Longer exposure may result from a drug’s slower metabolism when taken at night, for instance, theophylline clearance is slower at night [8]. Because hepatic enzymes’ circadian rhythms mediate this diurnal variation in drug metabolism, dosing schedules must be carefully considered in order to maintain therapeutic concentrations and reduce toxicity. Bioavailability and tissue penetration may also be affected by time-dependent changes in drug distribution and absorption that are influenced by circadian rhythms [10]. In the end, these pharmacokinetic temporal dynamics highlight the need for customized chronotherapeutic regimens to take interpatient variation in drug disposition into consideration [11].
Pharmacodynamics: Hormones, enzymes, and receptors frequently exhibit their highest activity during particular periods. For example, in accordance with natural cortisol rhythms, glucocorticoid receptors are most responsive in the morning [58]. Drug efficacy is influenced by this rhythmic sensitivity, which makes chronotherapeutic interventions possible to maximize desired physiological responses and reduce adverse drug reactions [8]. By ensuring that drug administration coincides with the body’s peak responsiveness, this synchronization maximizes therapeutic outcomes while minimizing potential side effects. Therefore, this method requires a deep comprehension of the complex interactions between endogenous circadian oscillators and pharmaceutical agents [59].
Challenges in Chronotherapy
A lot of challenges are facing chronotherapy, although the accelerated implications, potentials, and advances in this field. Hereby are examples of some challenges: Patient Adherence: patient compliance and adherence are greatly associated with once daily dosing, while the polypharmacy and complicated schedules could make people less compliant [37]. Additionally, people who work shifts or have different daily routines may find it difficult to meet the requirement for exact timing.
Individual Variability
Circadian rhythms are influenced by genetics, lifestyle, and chronotype (morning larks vs. night owls), which makes it challenging to make general recommendations [60]. This intrinsic variability emphasizes the necessity of customized chronotherapeutic approaches based on each patient’s unique physiological rhythms rather than universal recommendations [4]. Healthcare System Limitations: Clinics and hospitals frequently follow set schedules rather than the needs of their patients requires [37]. The application of chronotherapy may be hampered by this structural rigidity since it might not coincide with the best times for each patient to receive their medications, [61]. Drug Formulation: Not all medications come in forms that enable sustained release or adjustable timing [5]. To get around this restriction, it is essential to develop chronomodulated drug delivery systems, like pulsatile release formulations, which allow for precise temporal drug delivery in accordance with circadian rhythms [62]. Additionally, a major obstacle to chronotherapy’s broad acceptance and efficient application in patient care is the absence of established procedures for incorporating it into standard clinical practice [63]. Clinical Evidence: Although chronotherapy is supported by numerous studies, there are currently few large-scale randomized controlled trials available for many diseases [5]. Because clinicians value evidence-based practices, this lack of solid clinical data frequently prevents widespread adoption. Digital Health Tools: By monitoring sleep, heart rate, and circadian markers, smartwatches and biosensors can help customize medication timing to suit personal schedules; Chronopharmacogenomics: Customizing treatment regimens may be possible by comprehending how genetic variations in clock genes impact drug metabolism [59]. Advanced mathematical modeling combined with wearable technology presents promising opportunities for real-time circadian rhythm monitoring, allowing for dynamically modified chronotherapy regimens [11, 64]. Additionally, there is a lot of promise for improving individualized chronotherapeutic approaches in the developing field of chronopharmacogenomics, which investigates how genetic variations in circadian clock genes affect drug metabolism and response [65, 66]. Chronotherapy is positioned as a crucial frontier in precision medicine due to the convergence of biological insights and technological advancements, which go beyond generalized dosing schedules to highly customized therapeutic interventions [67, 68]. Artificial Intelligence: AI algorithms may examine patient information to forecast the best time to take medication [5]. To dynamically optimize drug administration schedules, these models could incorporate a variety of datasets, such as physiological parameters, genetic predispositions, and environmental factors. A paradigm shift towards truly personalized medicine catered to each person’s distinct chronobiological profile could result from such developments, which could greatly increase therapeutic efficacy while simultaneously reducing side effects [6, 69]. Drug Delivery Systems: New formulations that can synchronize drug delivery with circadian patterns include chronomodulated release tablets and programmable pumps [48]. By coordinating drug exposure with biological rhythms, these cutting-edge systems maximize therapeutic benefit and minimize side effects through precise temporal drug release. For conditions ranging from cancer to cardiovascular diseases, where circadian rhythms significantly influence drug response and disease progression, this precision in drug delivery is essential for maximizing treatment efficacy [37, 70].

Limitations

The manuscript’s primary academic limitation is its nature as a narrative review that synthesizes existing literature rather than presenting new empirical data. Its conclusions are inherently constrained by the developing state of the chronotherapy field itself, which, as noted in the work, often lacks the large-scale randomized controlled trials necessary for widespread clinical adoption. Furthermore, the review details significant practical barriers that limit the real-world application of its concepts, including individual variability in circadian rhythms, challenges with patient adherence to complex schedules, the rigidity of healthcare systems, and the lack of suitable drug formulations.

Conclusion

In the end, chronotherapy has the potential to transform medicine from a static field to one that is dynamic and time-sensitive [71]. By utilizing the body’s natural rhythms, this paradigm shift has the potential to greatly enhance treatment outcomes and bring healthcare closer to being truly customized and optimized [56]. By incorporating their individual physiological timing into their treatment plans, this method not only improves therapeutic efficacy and lowers adverse drug reactions, but it also gives patients more control over their care [10,12].
Chronotherapy is an emerging medical paradigm shift, and it acts as a utility function for healthcare providers to enhance therapeutic results, reduce toxicity, and optimize medical care. Advances in chronobiology, technology, and pharmacology are opening the door for routine clinical application, despite ongoing challenges, especially in the areas of patient adherence, healthcare logistics, and customized timing. Chronotherapy serves as a reminder that medicine encompasses more than just illnesses and molecules; it also involves balancing with time.

References

1. Smith DF, Ruben MD, Francey LJ, Walch OJ, Hogenesch JB. When should you take your medicines? J Biol Rhythms. 2019;34(6):582-3. doi:10.1177/0748730419892099.
   Article PubMed Google Scholar
2. Aoyama S, Shibata S. Time-of-day-dependent physiological responses to meal and exercise. Front Nutr. 2020;7:18. doi:10.3389/fnut.2020.00018.
   Article PubMed Google Scholar
3. Paul JR, Rhoads MK, Elam A, Pollock DM, Gamble KL. High-salt diet increases suprachiasmatic neuronal excitability through endothelin receptor type B signaling. Function. 2025;6(2):14. doi:10.1093/function/zqaf014.
   Article PubMed Google Scholar
4. Nahmias Y, Androulakis IP. Circadian effects of drug responses. Annu Rev Biomed Eng. 2021;23(1):203-24. doi:10.1146/annurev-bioeng-082120-034725.
   Article PubMed Google Scholar
5. Patil J. Oral drug delivery via chronotherapy approach: need of the day. J Pharmacovigilance. 2017;05(02):1-2. doi:10.4172/2329-6887.1000e167.
   Article PubMed Google Scholar
6. Butler CT, Rodgers AM, Curtis AM, Donnelly RF. Chrono-tailored drug delivery systems: recent advances and future directions. Drug Deliv and Transl Res. 2024;14(7):1756-75.doi:10.1007/s13346-024-01539-4.
   Article PubMed Google Scholar
7. Nuszkiewicz J, Rzepka W, Markiel J, Porzych M, Woźniak A, Szewczyk-Golec K. Circadian rhythm disruptions and cardiovascular disease risk: The special role of melatonin. CIMB. 2025;47(8):664. doi:10.3390/cimb47080664.
   Article PubMed Google Scholar
8. Koyanagi S. Chrono-Pharmaceutical approaches to optimize dosing regimens based on the circadian clock machinery. Biol Pharm Bull. 2021;44(11):1577-84. doi:10.1248/bpb.b21-00476.
   Article PubMed Google Scholar
9. Vandenberghe A, Lefranc M, Furlan A. An overview of the circadian clock in the frame of chronotherapy: From bench to bedside. Pharmaceutics. 2022;14(7):1424. doi:10.3390/pharmaceutics14071424.
   Article PubMed Google Scholar
10. Yu F, Liu Y, Zhang R, Zhu L, Zhang T, Shi Y. Recent advances in circadian- regulated pharmacokinetics and its implications for chronotherapy. Biochem Pharmacol. 2022;203:115185. doi:10.1016/j.bcp.2022.115185.
    Article PubMed Google Scholar
11. Ballesta A, Innominato PF, Dallmann R, Rand DA, Lévi FA. Systems chronotherapeutics. Pharmacol Rev. 2017;69(2):161-99. doi:10.1124/ pr.116.013441.
    Article PubMed Google Scholar
12. Smolensky MH, Hermida RC, Geng YJ. Chronotherapy of cardiac and vascular disease: timing medications to circadian rhythms to optimize treatment effects and outcomes. Curr Opin Pharmacol. 2021;57:41-8. doi:10.1016/j. coph.2020.10.014.
    Article PubMed Google Scholar
13. Krakowiak K, Durrington HJ. The role of the body clock in asthma and COPD: Implication for treatment. Pulm Ther. 2018;4(1):29-43.doi:10.1007/s41030-018- 0058-6.
    Article PubMed Google Scholar
14. Patton AP, Hastings MH. The mammalian circadian time-keeping system. J Huntingtons Dis. 2023;12(2):91-104. doi:10.3233/JHD-230571.
    Article PubMed Google Scholar
15. Begemann K, Neumann A, Oster H. Regulation and function of extra-SCN circadian oscillators in the brain. Acta Physiologica. 2020;229(1):e13446. doi:10.1111/apha.13446.
    Article PubMed Google Scholar
16. Bazhanova ED. Desynchronosis: Types, main mechanisms, role in the pathogenesis of epilepsy and other diseases: A literature review. Life. 2022;12(8):1218. doi:10.3390/life12081218.
    Article PubMed Google Scholar
17. Bicker J, Alves G, Falcão A, Fortuna A. Timing in drug absorption and disposition: The past, present, and future of chronopharmacokinetics. British J Pharmacology. 2020;177(10):2215-39. doi:10.1111/bph.15017.
    Article PubMed Google Scholar
18. Chowdhury D, Wang C, Lu AP, Zhu HL. Understanding quantitative circadian regulations are crucial towards advancing chronotherapy. Cells. 2019;8(8):883. doi:10.3390/cells8080883.
    Article PubMed Google Scholar
19. Oster H, Van Der Horst GTJ, Albrecht U. Daily variation of clock output gene activation in behaviorally arrhythmic mPer / mCry triple mutant mice. Chronobiol Int. 2003;20(4):683-95. doi:10.1081/cbi-120022408.
    Article PubMed Google Scholar
20. Jarmusch AK, Vrbanac A, Momper JD, et al. Enhanced characterization of drug metabolism and the influence of the intestinal microbiome: A pharmacokinetic, microbiome, and untargeted metabolomics study. Clinical Translational Sci. 2020;13(5):972-84. doi:10.1111/cts.12785.
    Article PubMed Google Scholar
21. Piedras ALR, Sánchez UB, Hernández EGO, Romero AC. Chronopharmacokinetics: A brief analysis of the influence of circadian rhythm on the absorption, distribution, metabolism, and elimination of drugs. Biomed Pharmacol J. 2024;17(3):2011-7. doi:10.13005/bpj/3003.
    Article PubMed Google Scholar
22. Colita CI, Hermann DM, Filfan M, et al. Optimizing chronotherapy in psychiatric care: The impact of circadian rhythms on medication timing and efficacy. Clocks Sleep. 2024;6(4):635-55. doi:10.3390/clockssleep6040043.
    Article PubMed Google Scholar
23. Sletten TL, Cappuccio FP, Davidson AJ, Van Cauter E, Rajaratnam SMW, Scheer FAJL. Health consequences of circadian disruption. Sleep. 2020;43(1):zsz194. doi:10.1093/sleep/zsz194.
    Article PubMed Google Scholar
24. Dong D, Yang D, Lin L, Wang S, Wu B. Circadian rhythm in pharmacokinetics and its relevance to chronotherapy. Biochem Pharmacol. 2020;178:114045. doi:10.1016/j.bcp.2020.114045.
    Article PubMed Google Scholar
25. Erkekoglu P, Baydar T. Chronopharmacodynamics of drugs in toxicological aspects: A short review for clinical pharmacists and pharmacy practitioners. J Res Pharm Pract. 2012;1(2):41. doi:10.4103/2279-042X.108369.
    Article PubMed Google Scholar
26. Baraldo M. The influence of circadian rhythms on the kinetics of drugs in humans. Expert Opin Drug Metab Toxicol. 2008;4(2):175-92. doi:10.1517/17425255.4.2.175.
    Article PubMed Google Scholar
27. Ruben MD, Smith DF, FitzGerald GA, Hogenesch JB. Dosing time matters. Science. 2019;365(6453):547-9. doi:10.1126/science.aax7621.
    Article PubMed Google Scholar
28. Mermet J, Yeung J, Naef F. Systems chronobiology: Global analysis of gene regulation in a 24-Hour periodic world. Cold Spring Harb Perspect Biol. 2017;9(3):a028720. doi:10.1101/cshperspect.a028720.
    Article PubMed Google Scholar
29. Zeng Y, Guo Z, Wu M, Chen F, Chen L. Circadian rhythm regulates the function of immune cells and participates in the development of tumors. Cell Death Discov. 2024;10(1):199. doi:10.1038/s41420-024-01960-1.
    Article PubMed Google Scholar
30. Franzago M, Alessandrelli E, Notarangelo S, Stuppia L, Vitacolonna E. Chrono- nutrition: Circadian rhythm and personalized nutrition. IJMS. 2023;24(3):2571. doi:10.3390/ijms24032571.
    Article PubMed Google Scholar
31. Sardon Puig L, Valera-Alberni M, Cantó C, Pillon NJ. Circadian rhythms and mitochondria: Connecting the dots. Front Genet. 2018;9:452. doi:10.3389/ fgene.2018.00452.
    Article PubMed Google Scholar
32. Khodasevich D, Tsui S, Keung D, Skene DJ, Revell V, Martinez ME. Characterizing the modern light environment and its influence on circadian rhythms. Proc R Soc B. 2021;288(1955):0721. doi:10.1098/rspb.2021.0721.
    Article PubMed Google Scholar
33. Festus ID, Spilberg J, Young ME, et al. Pioneering new frontiers in circadian medicine chronotherapies for cardiovascular health. TEM. 2024;35(7):607-23. doi:10.1016/j.tem.2024.02.011.
    Article PubMed Google Scholar
34. Portaluppi F, Lemmer B. Chronobiology and chronotherapy of ischemic heart disease. Adv Drug Deliv Rev. 2007;59(9-10):952-65. doi:10.1016/j. addr.2006.07.029.
    Article PubMed Google Scholar
35. Tsimakouridze EV, Alibhai FJ, Martino TA. Therapeutic applications of circadian rhythms for the cardiovascular system. Front Pharmacol. 2015;6:77. doi:10.3389/fphar.2015.00077.
    Article PubMed Google Scholar
36. Soares AC, Fonseca DA. Cardiovascular diseases: a therapeutic perspective around the clock. Drug Discov. Today. 2020;25(6):1086-98. doi:10.1016/j. drudis.2020.04.006.
    Article PubMed Google Scholar
37. Vijayan AS, R S, G BJ, Samuel J. A Review on chronotherapy, a time programmed drug delivery. IJPSRR. 2020;64(1):173-8. doi:10.47583/ijpsrr.2020.v64i01.031.
    Article PubMed Google Scholar
38. Amiama-Roig A, Verdugo-Sivianes EM, Carnero A, Blanco JR. Chronotherapy: Circadian rhythms and their influence in cancer therapy. Cancers. 2022;14(20):5071. doi:10.3390/cancers14205071.
    Article PubMed Google Scholar
39. Tang Q, Xie M, Yu S, et al. Periodic Oxaliplatin administration in synergy with PER2-mediated PCNA transcription repression promotes chronochemotherapeutic efficacy of OSCC. Adv Sci. 2019;6(21):1900667. doi:10.1002/advs.201900667.
    Article PubMed Google Scholar
40. Giacchetti S, Bjarnason G, Garufi C, et al. Phase III trial comparing 4-Day chronomodulated therapy versus 2-Day conventional delivery of Fluorouracil, Leucovorin, and Oxaliplatin as first-line chemotherapy of metastatic colorectal cancer. JCO. 2006;24(22):3562-9. doi:10.1200/JCO.2006.06.1440.
    Article PubMed Google Scholar
41. Kilgallen AB, Štibler U, Printezi MI, et al. Comparing conventional chemotherapy to chronomodulated chemotherapy for cancer treatment: Protocol for a systematic review. JMIR Res Protoc. 2020;9(10):e18023.doi:10.2196/18023.
    Article PubMed Google Scholar
42. Paudel KR, Jha SK, Allam VSRR, et al. Recent advances in chronotherapy targeting respiratory diseases. Pharmaceutics. 2021;13(12):2008. doi:10.3390/ pharmaceutics13122008.
    Article PubMed Google Scholar
43. Matejko B, Kukułka A, Kieć-Wilk B, Stąpór A, Klupa T, Malecki MT. Basal Insulin dose in adults with type 1 Diabetes Mellitus on Insulin pumps in real- life clinical practice: A single-center experience. Adv Med. 2018;2018:1-5. doi:10.1155/2018/1473160.
    Article PubMed Google Scholar
44. Fujimoto R, Ohta Y, Masuda K, et al. Metabolic state switches between morning and evening in association with circadian clock in people without diabetes. J of Diabetes Invest. 2022;13(9):1496-505. doi:10.1111/jdi.13810.
    Article PubMed Google Scholar
45. Dollet L, Pendergrast LA, Zierath JR. The role of the molecular circadian clock in human energy homeostasis. Curr Opin Lipidol. 2021;32(1):16-23. doi:10.1097/ MOL.0000000000000722.
    Article PubMed Google Scholar
46. Fuad SA, Ginting RP, Lee MW. Chrononutrition: Potential, challenges, and application in managing obesity. IJMS. 2025;26(11):5116. doi:10.3390/ ijms26115116.
    Article PubMed Google Scholar
47. Parravano M, Eandi C, Figus M, et al. Effects of circadian rhythm disruption on retinal physiopathology: Considerations from a consensus of experts. Eur J Ophthalmol. 2022;32(5):2489-93. doi:10.1177/11206721221106149.
    Article PubMed Google Scholar
48. Mallamma T, Prakash Goudanavar, Nagaraja Sreeharsha, Santosh Fattepur. Chrono modulated therapy-A review. IJRPS. 2020;11(SPL4):2884-90. doi:10.26452/ijrps.v11iSPL4.4575.
    Article PubMed Google Scholar
49. Ahmad F, Sachdeva P, Sarkar J, Izhaar R. Circadian dysfunction and Alzheimer’s disease - An updated review. Aging Med (Milton). 2023;6(1):71-81. doi:10.1002/agm2.12221.
    Article PubMed Google Scholar
50. Cummings J. New approaches to symptomatic treatments for Alzheimer’s disease. Mol Neurodegeneration. 2021;16(1):2. doi:10.1186/s13024-021-00424- 9.
    Article PubMed Google Scholar
51. Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer’s disease drug development pipeline. Clin Interv. 2024;10(2):e12465. doi:10.1002/ trc2.12465.
    Article PubMed Google Scholar
52. Fishbein AB, Knutson KL, Zee PC. Circadian disruption and human health. J Clin Invest. 2021;131(19):e148286. doi:10.1172/JCI148286.
    Article PubMed Google Scholar
53. Rajput A, Pingale P, Telange D, Musale S, Chalikwar S. A current era in pulsatile drug delivery system: Drug journey based on chronobiology. Heliyon. 2024;10(10):e29064. doi:10.1016/j.heliyon.2024.e29064.
    Article PubMed Google Scholar
54. Anusha V, Umashankar MS, Kumar YG. Pulsatile drug delivery system — an innovative method to treat chronotherapeutic diseases by synchronizing drug delivery with circadian rhythm. J Appl Pharm Sci. 2023:13(12):066-078. doi:10.7324/JAPS.2023.125025.
    Article PubMed Google Scholar
55. Ding J, Chen P, Qi C. Circadian rhythm regulation in the immune system. Immunology. 2024;171(4):525-33. doi:10.1111/imm.13747.
    Article PubMed Google Scholar
56. Cederroth CR, Albrecht U, Bass J, et al. Medicine in the fourth dimension. Cell Metabolism. 2019;30(2):238-50. doi:10.1016/j.cmet.2019.06.019.
    Article PubMed Google Scholar
57. Ayyar VS, Sukumaran S. Circadian rhythms: influence on physiology, pharmacology, and therapeutic interventions. J Pharmacokinet Pharmacodyn. 2021;48(3):321-38. doi:10.1007/s10928-021-09751-2.
    Article PubMed Google Scholar
58. Scherholz ML, Schlesinger N, Androulakis IP. Chronopharmacology of glucocorticoids. Adv Drug Deliv Rev. 2019;151-152:245-61. doi:10.1016/j. addr.2019.02.004.
    Article PubMed Google Scholar
59. Ohdo S, Koyanagi S, Matsunaga N. Chronopharmacological strategies focused on chrono-drug discovery. Pharmacology & Therapeutics. 2019;202:72-90. doi:10.1016/j.pharmthera.2019.05.018.
    Article PubMed Google Scholar
60. Mentzelou M, Papadopoulou SK, Papandreou D, et al. Evaluating the relationship between circadian rhythms and sleep, metabolic and cardiovascular disorders: Current clinical evidence in human studies. Metabolites. 2023;13(3):370. doi:10.3390/metabo13030370.
    Article PubMed Google Scholar
61. Selfridge JM, Gotoh T, Schiffhauer S, et al. Chronotherapy: Intuitive, sound, founded…but not broadly applied. Drugs. 2016;76(16):1507-21. doi:10.1007/ s40265-016-0646-4.
    Article PubMed Google Scholar
62. Sajan J, Cinu T, Chacko A, Litty J, Jaseeda T. Chronotherapeutics and chronotherapeutic drug delivery systems. Trop J Pharm Res. 2009;8(5): 467-75. doi:10.4314/tjpr.v8i5.48091.
    Article PubMed Google Scholar
63. Walton JC, Walker WH, Bumgarner JR, et al. Circadian variation in efficacy of medications. Clin Pharma and Therapeutics. 2021;109(6):1457-88. doi:10.1002/ cpt.2073.
    Article PubMed Google Scholar
64. Kim DW, Zavala E, Kim JK. Wearable technology and systems modeling for personalized chronotherapy. Curr Opin Syst Biol. 2020;21:9-15. doi:10.1016/j. coisb.2020.07.007.
    Article PubMed Google Scholar
65. Achari KV. Chronobiology and chrono pharmacology with reference to consequences and management of shift work. JMPAS. 2022;11(1):4087-92. doi:10.22270/jmpas.V11I1.1105.
    Article PubMed Google Scholar
66. Youan BBC. Chronopharmaceutics: gimmick or clinically relevant approach to drug delivery? J Control Release. 2004;98(3):337-53. doi:10.1016/j. jconrel.2004.05.015.
    Article PubMed Google Scholar
67. Kaşkal M, Sevim M, Ülker G, Keleş C, Bebitoğlu BT. The clinical impact of chronopharmacology on current medicine. Naunyn Schmiedebergs Arch Pharmacol. 2025;398(6):6179-91. doi:10.1007/s00210-025-03788-7.
    Article PubMed Google Scholar
68. Dobrek L. Chronopharmacology in therapeutic drug monitoring—dependencies between the rhythmics of pharmacokinetic processes and drug concentration in blood. Pharmaceutics. 2021;13(11):1915. doi:10.3390/pharmaceutics13111915.
    Article PubMed Google Scholar
69. Sewlall S, Pillay V, Danckwerts MP, Choonara YE, Ndesendo VM, du Toit LC. A Timely review of state-of-the-art chronopharmaceuticals synchronized with biological rhythms. CDD. 2010;7(5):370-88. doi:10.2174/156720110793566236.
    Article PubMed Google Scholar
70. Mandal AS, Biswas N, Karim KM, et al. Drug delivery system based on chronobiology—A review. J Control Release. 2010;147(3):314-25. doi:10.1016/j. jconrel.2010.07.122.
    Article PubMed Google Scholar
71. Fey RM, Billo A, Clister T, et al. Personalization of cancer treatment: Exploring the Role of Chronotherapy in Immune Checkpoint Inhibitor Efficacy. Cancers. 2025;17(5):732. doi:10.3390/cancers17050732.
    Article PubMed Google Scholar

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