Nonlinear dynamics in clinical pharmacology: the paradigm of cortisol secretion and suppression.

Abstract

The proper use of a medicinal agent is based on its pharmacokinetic (PK) and pharmacodynamic (PD) characteristics. However, PK and PD parameters are subject to considerable intra- and inter-subject variability. Careful analyses during the last decade revealed that PDs is definitely more variable than PKs [1]. It is generally believed that the determinants of PD variability are unknown since the factors affecting concentration-response relationships are numerous [2]. This idea relies on the classical, stochastic view of randomness. However, over the last two decades the science of nonlinear dynamics has shown that complex-random looking behaviour can be generated by deterministic systems [3]. Although only classical randomness is clearly involved in most PD studies, e.g. chemotherapy, a considerable part of the variability in some PD studies, e.g. cardiovascular, CNS, hormonal, may originate from a nonlinear system with even a few degrees of freedom [4]. This argument relies on the principles of nonlinear dynamics [5] as applied to complex biological systems [6–8]. In addition, the ligand–receptor interaction exhibits nonlinear dynamic behaviour when feedback mechanisms are involved [9, 10]. One of the physiological processes where nonlinear dynamics is believed to play an important role is the secretion of hormones. The erratic behaviour of hormone secretion originates from the complex dynamics involved. Numerous applications of nonlinear dynamics to the secretion of hormones have been published [11–17]. In this context, various methods for the analysis of the chaotic nature of the pulsatile secretion of hormones have been reported [18–20]. In the following sections we present a brief summary of the basic properties of a dynamical system and an example of a nonlinear dynamical model which describes erratic plasma cortisol concentrations, as well as the effect of corticosteroids upon them. The latter gives an opportunity to discuss the concept of variability in PK and PD studies from a dynamical systems' perspective.