Changes in toxicity and effectiveness with timing of drug administration: implications for drug safety

The effectiveness and toxicity of many drugs can vary depending on the time of administration in relation to 24-hour rhythms of biochemical, physiological and behavioural processes under the control of the circadian clock. Such chronopharmacological phenomena are influenced by not only the pharmacokinetics but also pharmacodynamics of medications. Chronotherapy is especially relevant when the risk and/or intensity of the symptoms of disease vary predictably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke and peptic ulcer disease. Morning, once-daily administration of corticosteroids results in little adrenocortical suppression, while the same daily dose split into four equal doses to coincide with daily meals and bedtime results in significant hypothalamus-pituitary-adrenal axis suppression. In a randomised, multicentre trial involving patients with previously untreated metastases from colorectal cancer, the chronomodulated infusion of oxaliplatin, fluorouracil and folinic acid was compared with a constant-rate infusion method. Adverse effects such as stomatitis and peripheral sensory neuropathy were lower and objective response was higher with chronotherapy as compared with the fixed-rate infusion. The merit of chronomodulated infusion is supported by the 24-hour rhythm of DNA synthesis and the activity of dehydropyrimidine dehydrogenase, which brings about the intracellular catabolism of fluorouracil. On the other hand, haloperidol and selective serotonin reuptake inhibitors have diverse effects on sleep continuity and nocturnal arousals. Although interferon also alters the clock function, this disruptive effect can be overcome by devising an administration regimen that minimises adverse drug effects on clock function. Thus, one approach to increasing the efficiency of pharmacotherapy is the administration of drugs at times at which they are most effective and/or best tolerated.