Chronopharmacology

Joke Meijer (LUMC)

Chronopharmacological studies have revealed circadian variability in pharmacokinetics (PK) and dynamics of clinically used drugs. For instance, PK parameters of several non-steroidal anti-inflammatory drugs vary as a function of dosing time, and serum concentrations of several anti-cancer and anti-asthma drugs show significant daily fluctuations despite a constant intravenous infusion rate. Drug administration at the right time of the day, adjusted to the individual circadian phase, is likely to improve the outcome of pharmacotherapy, leading to improved therapeutic efficiency, decreased toxicity (less adverse effects), and/or lower drug dosing. Despite growing interest in this topic, the moment of administration of a drug is often neglected in clinical settings.

Time-dependent changes in PK may proceed from circadian variations in absorption, distribution, metabolism and/or excretion, Ideally, research on circadian rhythmicity should address all these determinants but few studies have assessed more than one of the PK properties of drugs Here we propose to study daily rhythms on all relevant PK parameters simultaneously. By choosing appropriate model drugs, we are able to study absorption, pre-hepatic clearance, drug delivery to clearing organs (renal, liver blood flow, etc), drug metabolizing enzymes and transporters, and drug (or metabolite) excretion, as a function of time of day.