Chronotherapy, Cancers and Transplantation Research Unit, Faculty of Medicine, Paris-Saclay University, Villejuif, France; email:
Gastrointestinal and General Oncology Service, Paul-Brousse Hospital, Assistance Publique-Hôpitaux de Paris, Villejuif, France.
Annu Rev Pharmacol Toxicol. 2024 Jan 23;64:89-114. doi: 10.1146/annurev-pharmtox-051920-095416. Epub 2023 Sep 18.
Today's challenge for precision medicine involves the integration of the impact of molecular clocks on drug pharmacokinetics, toxicity, and efficacy toward personalized chronotherapy. Meaningful improvements of tolerability and/or efficacy of medications through proper administration timing have been confirmed over the past decade for immunotherapy and chemotherapy against cancer, as well as for commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, and neurological conditions. Experimental and human studies have recently revealed sexually dimorphic circadian drug responses. Dedicated randomized clinical trials should now aim to issue personalized circadian timing recommendations for daily medical practice, integrating innovative technologies for remote longitudinal monitoring of circadian metrics, statistical prediction of molecular clock function from single-timepoint biopsies, and multiscale biorhythmic mathematical modelling. Importantly, chronofit patients with a robust circadian function, who would benefit most from personalized chronotherapy, need to be identified. Conversely, nonchronofit patients could benefit from the emerging pharmacological class of chronobiotics targeting the circadian clock.
当今精准医学面临的挑战涉及到分子钟对药物药代动力学、毒性和疗效的个体化时辰治疗的影响。在过去十年中，通过适当的给药时间，免疫疗法和癌症化疗以及心血管、代谢、炎症和神经疾病中常用的药理学药物已经证实了药物耐受性和/或疗效的显著改善。实验和人体研究最近揭示了性二态昼夜节律药物反应。现在，专门的随机临床试验应该旨在为日常医疗实践发布个性化的昼夜时间建议，整合远程纵向监测昼夜节律指标的创新技术、从单次活检预测分子钟功能的统计预测以及多尺度生物节律数学模型。重要的是，需要识别出具有稳健生物钟功能的 Chronofit 患者，他们将从个体化时辰治疗中获益最多。相反，非 Chronofit 患者可能受益于新兴的生物钟药物类，这些药物针对生物钟。
