Circadian Rhythms in Drug Response: From Molecular Clocks to Precision Dosing

Abstract

Circadian rhythms organize mammalian physiology across the 24-h day through molecular clocks coordinated by the central clock in the suprachiasmatic nucleus and distributed to peripheral oscillators. These clocks regulate processes central to pharmacology, including drug absorption, distribution, metabolism, elimination, and target responsiveness. Consequently, drug efficacy and toxicity can vary substantially depending on the time of administration. Despite decades of progress in pharmacogenomics and systems pharmacology, consideration of time of day remains largely absent from clinical drug development and prescription. In this review, we evaluate emerging research on circadian regulation of drug responses, considering both pharmacokinetics and pharmacodynamics. We review chronotherapeutic strategies to treat diseases, including cancer, cardiovascular disease, and bipolar disorder. We also discuss the use of wearable technologies to enable time-resolved drug evaluation. Finally, we discuss the challenges to clinical translation and the integration of circadian timing into precision medicine and optimized dosing strategies.