Abstract
We recently described rapid quantitative pharmacodynamic imaging, a novel method for estimating sensitivity of a biological system to a drug. We tested its accuracy in simulated biological signals with varying receptor sensitivity and varying levels of random noise, and presented initial proof-of-concept data from functional MRI (fMRI) studies in primate brain. However, the initial simulation testing used a simple iterative approach to estimate pharmacokinetic-pharmacodynamic (PKPD) parameters, an approach that was computationally efficient but returned parameters only from a small, discrete set of values chosen a priori. Here we revisit the simulation testing using a Bayesian method to estimate the PKPD parameters. This improved accuracy compared to our previous method, and noise without intentional signal was never interpreted as signal. We also reanalyze the fMRI proof-of-concept data. The success with the simulated data, and with the limited fMRI data, is a necessary first step toward further testing of rapid quantitative pharmacodynamic imaging.
Highlights
Measuring the sensitivity of an organ to a drug in vivo is a common, important research goal
We recently described a novel method, rapid quantitative pharmacodynamic imaging, for estimating sensitivity of a biological system to a drug in a single measurement session using repeated small doses of drug (Black et al, 2013)
Accuracy Accuracy of the EC50 estimate was considered for time courses with prob(model) >0.5
Summary
Measuring the sensitivity of an organ to a drug in vivo is a common, important research goal. The traditional approach is to independently measure biological responses to a range of different doses of drug. We recently described a novel method, rapid quantitative pharmacodynamic imaging (or QuanDynTM), for estimating sensitivity of a biological system to a drug in a single measurement session using repeated small doses of drug (Black et al, 2013). We tested QuanDynTM’s accuracy in simulated data with varying receptor sensitivity and varying levels of random noise. The initial simulation testing used a simple iterative approach to estimate pharmacokinetic-pharmacodynamic (PKPD) parameters including EC50, the plasma concentration of drug that produces half the maximum possible effect Emax. The iterative approach was computationally efficient but could only select EC50 from a short list of parameter values chosen a priori
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