Understanding the Hysteresis Loop Conundrum in Pharmacokinetic / Pharmacodynamic Relationships

Abstract

Hysteresis loops are phenomena that sometimes are encountered in the analysis of pharmacokinetic and pharmacodynamic relationships spanning from pre-clinical to clinical studies. When hysteresis occurs it provides insight into the complexity of drug action and disposition that can be encountered. Hysteresis loops suggest that the relationship between drug concentration and the effect being measured is not a simple direct relationship, but may have an inherent time delay and disequilibrium, which may be the result of metabolites, the consequence of changes in pharmacodynamics or the use of a non-specific assay or may involve an indirect relationship. Counter-clockwise hysteresis has been generally defined as the process in which effect can increase with time for a given drug concentration, while in the case of clockwise hysteresis the measured effect decreases with time for a given drug concentration. Hysteresis loops can occur as a consequence of a number of different pharmacokinetic and pharmacodynamic mechanisms including tolerance, distributional delay, feedback regulation, input and output rate changes, agonistic or antagonistic active metabolites, uptake into active site, slow receptor kinetics, delayed or modified activity, time-dependent protein binding and the use of racemic drugs among other factors. In this review, each of these various causes of hysteresis loops are discussed, with incorporation of relevant examples of drugs demonstrating these relationships for illustrative purposes. Furthermore, the effect that pharmaceutical formulation has on the occurrence and potential change in direction of the hysteresis loop, and the major pharmacokinetic / pharmacodynamic modeling approaches utilized to collapse and model hysteresis are detailed.

Relationship between discriminative stimulus effects and plasma methamphetamine and amphetamine levels of intramuscular methamphetamine in male rhesus monkeys

“…Furthermore, in the case of methamphetamine, plasma amphetamine levels peaked at 300 min post-methamphetamine administration when responding was predominantly on the saline-associated key. These findings, together with a clockwise hysteresis loop (Louizos et al , 2014) suggest that acute tolerance may have developed to the methamphetamine-like discriminative stimulus effects after both methamphetamine and amphetamine administration. Acute tolerance to the behavioral and cardiovascular effects of methamphetamine and amphetamine has also been reported in humans (Angrist et al , 1987, Brauer et al , 1996, Kirkpatrick et al , 2012) and dogs (Vidrio, 1982).…”

“…To the best of our knowledge, there are no human or preclinical studies that have determined the role of the methamphetamine metabolite amphetamine in methamphetamine-induced behavioral effects. If methamphetamine metabolism to amphetamine contributed to or mediated the discriminative stimulus effects of methamphetamine in rhesus monkeys, we would predict a counter-clockwise hysteresis loop (Louizos et al , 2014) between methamphetamine-like discriminative stimulus effects and amphetamine plasma levels similar to a counter-clockwise hysteresis loop between cocaine-like discriminative stimulus effects and amphetamine plasma levels after lisdexamfetamine administration (Banks et al , 2015). …”

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

“…7). Several reasons could explain this delay (Louizos et al, 2014), such as the time needed for receptor-activated signal transduction, a rapid sensitization of receptors, or formation of metabolites with agonist activity. The latter possibility is unlikely, considering the low BBB passage and the brain PK profile of the main metabolite (M2).…”

Pharmacokinetic/pharmacodynamic evaluation of grapiprant in a carrageenan‐induced inflammatory pain model in the rabbit

“…However, this assumption may not be correct because the drug concentrations change as a result of the innate pharmacokinetics of the drug, and the pharmacodynamics could also change independently or in an opposite direction to the drug concentration. A variety of factors (distribution delay into the site of effect, slow receptor kinetics, delayed or modified pharmacological activity, the presence of active agonist metabolites and indirect physiological response) that might have affected the hysteresis shape have been previously reported in the literature (Louizos et al ., ). Further studies are warranted to clarify this issue.…”