2005 Annual Scientific Meeting - CLICK FOR PROGRAMME

Chronobiology and PK/PD modelling in anaesthesia

 Björn Lemmer

Institute of Pharmacology & Toxicology, Ruprecht-Karls-University of Heidelberg

e-mail: bjoern.lemmer@urz.uni-heidelberg.de

Chronobiological Background

Circadian rhythms have been documented throughout the plant and animal kingdom at every level of eukariotic organization. Circadian rhythms by definition are endogenous in nature, driven by oscillators or clocks, and persist under free-running conditions. In various species (Drosophila melongaster, Neurospora, Mouse, Golden hamster) the genes control­ling circadian rhythms have been identi­fied (genes: per, frq, clock, tau). Recently, clock genes were identified even in human tissues such as the skin and the mucosa. In general, the endogenous clock in man does not exactly runs at a frequency of 24 hours but some­what slower. Environmental time cues or Zeitgebers entrain the circadian rhythm to a precise 24-hour period. Most important to note that endogenous biological rhythms are anticipatory in nature! Thus, rhythmicity inherent to all living systems, allows them to adapt more easily and to better survive under changing environmental conditions during the 24 hours of a day as well as during varying conditions of the changing seasons.

Chronokinetics - Chronodynamics

It is still a common paradigm in clinical pharmacology that pharmacokinetic parameters as well as drug effects are considered not to be influenced by the time of day of drug administration. However, it is now well established that nearly all functions of the body, including those influencing pharmacokinetic parameters, display significant daily variations. In man the organization in time can also be seen in certain states of disease in which the onset and symptoms do not occur at random within 24 hours of a day, e.g. asthma attacks, coronary infarction, angina pectoris, rheumatic symptoms and pain in osteoarthritis, post operation and tooth pain.

There are data in experimental animals and in man demonstrating that drugs of different classes used for pain treatment – local anesthetics, NSAIDs, opioids, and placebo – cannot only display significant variations in their pharmacokinetis but also in the analgesic effects. In rodents, even the concentrations of endogenous opioids such as endorphins and enkephalins, were shown to be rhythmic.

Conclusions

Over the last years numerous clinical studies in various diseases including perception and treatment of pains have demonstrated that the pharmacokinetics and/or the effects of drugs can greatly depend on the time of day/circadian dosing time leading to a circadian phase-dependency in the dose response relationship. This can result in a dissociation between a drug's pharmacokinetic and pharmacodynamic profiles, PK/PD-modelling has to take into account this circadian phase dependency. Thus, not only must the right amount of the right substance be at the right place, but also this must occur at the right time.

References

1.       Lemmer, B., & Bruguerolle, B. (1994). Chronopharmacokinetics - are they clinically relevant? Clin Pharmacokinet 26, 419-427.

2.       Redfern, & B. Lemmer (Eds) (1997). Handbook of Experimental Pharmacology Vol 125 "Physiology and Pharmacology of Biological Rhythms". Heidelberg, New York: Springer.

3.       Lemmer, B. (2005). Chronopharmacology and controlled drug release. Exp Opin Drug Deliv 2, 667-681.