Rapid quantitative pharmacodynamic imaging by a novel method: theory, simulation testing and proof of principle.
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 EC 50 (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 EC 50 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 EC 50 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.
Departments of Psychiatry, Neurology, Radiology, and Anatomy & Neurobiology, Washington University School of Medicine , St. Louis, MO , USA.
Kevin J
KJ
Black
Jonathan M
JM
Koller
Brad D
BD
Miller
Dose-finding; Drug development; EC50; ED50; Neuroimaging; Pharmacodynamics; Pharmacokinetic-pharmacodynamic modeling; Pharmacological fMRI; fMRI; phMRI