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Circadian clocks and drug delivery systems: impact and opportunities in chronotherapeutics

Chronotherapeutics aims at the adjustment of treatments to ∼ 24 h rhythms, which result from the moderation of most biological functions by the circadian timing system (CTS). The integration of CTS-related knowledge in drug delivery concepts challenges most current views, where steady-state constant drug levels are synonymous to enhanced tolerability and efficacy. In contrast, robust molecular clocks rhythmically control Phase I, II and III drug metabolism, as well as pharmacodynamics. Thus, circadian timing of medications predictably modifies drug tolerability and/or efficacy up to several-fold in rodents, as well as in patients. Optimal dosing times indeed complement the recommendations for optimal doses of glucocorticoids, NSAIDs, bronchodilators and so on. Clinically-driven in vitro and in silico circadian data now provide mechanistic insights for the effective translation of chronotherapeutic delivery, especially for cancer therapies. Programmable-in-time electronic or polymeric drug delivery systems are being used for improving health in patients with cancer or rheumatoid diseases, respectively. Current research aims at the optimization of circadian amplitude and phase of drug delivery according to CTS biomarkers. Intelligent drug delivery systems could then integrate the critical rhythmic information stemming from the individual patient and achieve a critical leap forward in the safe administration of potentially toxic therapeutic agents.