Chronopharmacological aspects of PK/PD modelling.

Nearly all physiological functions as well as pathophysiological events display reproducible rhythmic changes within 24 hours of a day, including the cardiovascular system. Clinical chronopharmacological studies with antihypertensive drugs gave evidence that effects on the rhythms in blood pressure and heart rate are also dependent on the time of day. Chronopharmacokinetic studies with propranolol, oxprenolol, nifedipine, verapamil, etc. also revealed daily variations in the drugs' kinetics. In general, Cmax was higher and/or tmax shorter after morning than evening dosing of these rather lipophilic drugs. However, independently of whether or not daily variations in the kinetics were found the dose-response relationship was always dependent on the time of day. These data demonstrate that PK/PD modelling has to take into account reproducible rhythmic variations both in the kinetics and/or effects of cardiovascular active drugs.