Rapid quantitative pharmacodynamic imaging by a novel method: theory, simulation testing and proof of principle

Kevin J Black,Brad D Miller,Jonathan M Koller

doi:10.7717/peerj.117

Abstract

Pharmacological challenge imaging has mapped, but rarely quantified, the sensitivity of a biological system to a given drug. We describe a novel method called rapid quantitative pharmacodynamic imaging. This method combines pharmacokinetic-pharmacodynamic modeling, repeated small doses of a challenge drug over a short time scale, and functional imaging to rapidly provide quantitative estimates of drug sensitivity including EC50 (the concentration of drug that produces half the maximum possible effect). We first test the method with simulated data, assuming a typical sigmoidal dose-response curve and assuming imperfect imaging that includes artifactual baseline signal drift and random error. With these few assumptions, rapid quantitative pharmacodynamic imaging reliably estimates EC50 from the simulated data, except when noise overwhelms the drug effect or when the effect occurs only at high doses. In preliminary fMRI studies of primate brain using a dopamine agonist, the observed noise level is modest compared with observed drug effects, and a quantitative EC50 can be obtained from some regional time-signal curves. Taken together, these results suggest that research and clinical applications for rapid quantitative pharmacodynamic imaging are realistic.

Highlights

Many important biological problems involve measuring sensitivity to a specific drug
At high levels of noise, e.g., standard deviation (SD) > 0.5Emax, the model rarely fit significantly better than the null hypothesis. (For comparison, different ratios of SD to Emax are shown in Fig. 4.) At realistic intermediate values of noise, the model fit better for lower EC50 values
Under a reasonable set of assumptions, this method returns the correct answer either if it claims a given region has high sensitivity to drug effect, or if noise is of modest magnitude relative to the drug-induced signal

Summary

Introduction

Many important biological problems involve measuring sensitivity to a specific drug. The answers are of interest to scientists, the pharmaceutical industry, patients and clinicians. A variety of approaches have been employed. Pharmacological imaging methods, the focus of this communication, can be grouped as addressing drug sensitivity via one of two broad, nonexclusive strategies: mapping (localizing) regions of the body or of an organ that are most sensitive to drug, or measuring (quantifying) sensitivity to drug. For many questions of interest, mapping is all that is required. One scientific example would be to identify in what part of the brain dopamine loss begins in Parkinson disease. Finding an occult cancer is a clinical example. Many methods have been employed for pharmacological mapping.

Methods

Results

Conclusion