Abstract
Traditionally, drug dosing is based on a concentration-response relationship estimated in a population. Yet, in specific individuals, decisions based on the population-level effects frequently result in over or under-dosing. Here, we interrogate the relationship between population-based and individual-based responses to anesthetics in mice and zebrafish. The anesthetic state was assessed by quantifying responses to simple stimuli. Individual responses dynamically fluctuated at a fixed drug concentration. These fluctuations exhibited resistance to state transitions. Drug sensitivity varied dramatically across individuals in both species. The amount of noise driving transitions between states, in contrast, was highly conserved in vertebrates separated by 400 million years of evolution. Individual differences in anesthetic sensitivity and stochastic fluctuations in responsiveness complicate the ability to appropriately dose anesthetics to each individual. Identifying the biological substrate of noise, however, may spur novel therapies, assure consistent drug responses, and encourage the shift from population-based to personalized medicine.
Highlights
One of the great promises of personalized medicine is the delivery of a maximally efficacious and minimally harmful dose of appropriate medication to every patient (Fitzgerald et al, 2006)
In every mouse, the outcome of the righting reflex (RR) test fluctuated over time at a fixed anesthetic concentration (Figure 2A) while the population response probability at 0.6% isoflurane remained stable over time (Figure 2B)
The fluctuations exhibit inertia – the animal is more likely to be stuck in its current state than to transition between states of responsiveness
Summary
One of the great promises of personalized medicine is the delivery of a maximally efficacious and minimally harmful dose of appropriate medication to every patient (Fitzgerald et al, 2006). Dosing decisions are based on the relationship between drug concentration and the magnitude of effect observed in a population expressed as the sigmoidal dose-response curve (Goodman, 1996). An implicit assumption of this approach is that population averages adequately reflect the processes operating within each individual patient. The population-based dose-response curve, in contrast, is a smooth graded function of drug concentration. In order to deliver on the promise of optimal drug dosing at the individual level, the relationship between individual binary responses and the population-based graded estimates of drug potency have to be more rigorously defined (KochWeser, 1975)
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