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

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