Novel methods for medicinal dosage determination and diagnosis

Abstract

The present invention is directed to systems and methods for diagnosing tissue abnormality or diseases, determining effective drug dosages, and monitoring therapeutic drug treatments. The methods and systems described utilize tissue imaging in situ and computer modeling.

1 . A method of planning treatment for a patient with Parkinson's Disease, the method comprising:
 a) administering to the patient with Parkinson's disease, one or more doses of levodopa;   b) collecting biological imaging data of one or more brain regions of the patient with Parkinson's disease in response to the one or more doses of levodopa administered in a), over a period of time where the response to levodopa has not reached a steady state, and   c) repeatedly measuring levodopa concentrations in a body fluid from the patient with Parkinson's disease, over the period of time,   d) fitting predetermined pharmacokinetic-pharmacodynamic models to the information from step b) and step c), to determine constant ke, or t½ eq;   e) comparing the constant ke, or t½ eq, to historical values from healthy humans, and, or patients with Parkinson's disease, and   f) wherein subsequent treatment of the patient with Parkinson's disease is determined based on the comparison in e).   
     
     
         2 . The method of  claim 1 , wherein the historical values are drawn from said patient with Parkinson's disease. 
     
     
         3 . The method of  claim 1 , wherein the imaging data is collected on a magnetic resonance imaging device. 
     
     
         4 . The method of  claim 1 , wherein the imaging data is collected on a magnetic resonance imaging device sensitive to a blood oxygen level dependent signal. 
     
     
         5 . The method of  claim 1 , wherein the imaging data is collected using Positron Emission Tomography. 
     
     
         6 . The method of  claim 1 , wherein the imaging data is collected on a Single Photon Emission Computed Tomography imaging device. 
     
     
         7 . The method of  claim 1 , wherein the imaging data consists of perfusion imaging collected on a magnetic resonance imaging device. 
     
     
         8 . A method for improving a measurement of quantitative pharmacodynamic parameters for levodopa therapy in a human with Parkinson's disease, the method comprising:
 a) administering to the human with Parkinson's disease a single dose of levodopa;   b) collecting biological imaging data of the human with Parkinson's disease's response to the single dose of levodopa administered in a), the biological imaging data comprising, brain activity images before, during, and after the single dose of levodopa is administered,   c) measuring levodopa plasma concentrations,   d) fitting predetermined pharmacokinetic-pharmacodynamic models to said data collected in b) and c) to determine the quantitative pharmacodynamic parameters for said single dose of levodopa, comprising:
 i) setting up fit parameters and choosing a fit method; 
 ii) computing best-fit parameters and their goodness of fit to the biological data using the selected fit method; 
 iii) computing the statistical significance of the best-fit parameters; and 
 iv) generating an output. 
 v) comparing the output to historical output from healthy humans, and, or patients with Parkinson's disease. 
   
     
     
         9 . The method of  claim 8 , wherein the historical output is drawn from said patient with Parkinson's disease. 
     
     
         10 . The method of  claim 8 , wherein the imaging data is collected on a magnetic resonance imaging device. 
     
     
         11  .The method of  claim 8 , wherein the imaging data is collected on a magnetic resonance imaging device sensitive to a blood oxygen level dependent signal. 
     
     
         12 . A method for improving a measurement of quantitative pharmacodynamic parameters for levodopa in a human with Parkinson's disease, the method comprising:
 a) administering to the human a single dose of levodopa;   b) collecting biological imaging data of the human with Parkinson's disease response to the single dose of levodopa administered in a), wherein, the biological imaging data consists of the response of the human with Parkinson's disease collected before, during and after levodopa is administered and   c) repeatedly measuring levodopa plasma concentrations   d) fitting said predetermined pharmacokinetic-pharmacodynamic models to said data, collected in b) and c) consisting of calculating an effect compartment rate constant value Ke that collapses the hysteresis curve to a dose-effect function, for the affected brain regions, and   e) comparing the effect compartment rate constant value Ke that collapses the hysteresis curve to a dose-effect function, for the affected brain regions, to the effect compartment rate constant value Ke that collapses the hysteresis curve to a dose-effect function for the affected brain regions in a group of humans suffering from Parkinson's, to determine the relative severity for the individual human suffering from Parkinson's disease.   
     
     
         13 . A method of improving a measurement of Parkinson's disease severity in an individual human, the method comprising:
 a) administering to the human with Parkinson's disease one or more doses of levodopa;   b) repeatedly collecting biological imaging data from one or more brain regions of the human with Parkinson's disease over a period of time during which the response to levodopa in the one or more brain regions has not reached a steady state;   c) repeatedly measuring levodopa concentrations in a body fluid from the patient with Parkinson's disease, over the period of time,   d) fitting predetermined pharmacokinetic-pharmacodynamic models to the information from step b) and step c), to determine the constants ke or t½ eq, and   e) comparing the constant ke or t½ eq to historical values of ke or t½ eq from healthy humans, and, or patients with Parkinson's disease.   
     
     
         14 . The method of  claim 13 , wherein the method is performed without data from a clinically measured response. 
     
     
         15 . The method of  claim 13 , wherein the historical values of ke or t½ eq from healthy patients, and or, patients with Parkinson's disease patients, consists of historical values of ke or t½ eq from said patient with Parkinson's disease. 
     
     
         16 . A method of improving a measurement of Parkinson's disease severity in one or more regions in the brain in an individual human with Parkinson's disease, the method comprising:
 a) administering to the human with Parkinson's disease one or more doses of levodopa;   b) repeatedly collecting biological imaging data of one or more brain regions of the human with Parkinson's disease over a period of time during which the response to levodopa has not reached a steady state;   c) repeatedly measuring levodopa concentrations in a body fluid from the patient with Parkinson's disease, over the period of time;   d) fitting predetermined pharmacokinetic-pharmacodynamic models to the information from step b) and step c), to determine the constants ke or t½ eq; and   e) comparing the constant ke or t½ eq to known values of ke or t½ eq from healthy humans, and, or patients with Parkinson's disease.   
     
     
         17 . The method of  claim 16 , wherein the known values of ke or t½ eq are drawn from said patient with Parkinson's disease. 
     
     
         18 . The method of  claim 16  in which severity of Parkinson's disease is determined simultaneously for more than one brain regions. 
     
     
         19 . A method of improving a determination of the rate of progression of Parkinson's disease in a human with Parkinson's disease, the method comprising:
 a) performing non-concurrently, on each of two or more study days:
 i) administering to the human with Parkinson's disease one or more doses of levodopa; 
 ii) repeatedly collecting biological imaging data one or more brain regions of the human with Parkinson's disease over a period of time during which the response to levodopa has not reached a steady state; 
 iii) repeatedly measuring levodopa concentrations in a body fluid from the patient with Parkinson's disease, over the period of time, and 
   b) fitting predetermined pharmacokinetic-pharmacodynamic models to the information from each study day to determine the constants ke or t½ eq applying to that study day, and   c) computing the rate of progression of Parkinson's disease in the said human as the slope of the line that best fits the set of data points from all study days.   
     
     
         20 . A method of improving a determination of whether a medication or biological therapy slows a rate of Parkinson's disease progression, comprising:
 a) measuring the rate of progression of Parkinson's disease according to the method of claim  39  in a group of people with Parkinson's disease who are given the medication or biological therapy between the first and last study days, and   b) measuring the rate of progression of Parkinson's disease according to the method of claim  39  in a group of people with Parkinson's disease who are not given the medication or biological therapy between the first and last study days, and   c) comparing the rates of progression of Parkinson's disease between the two groups using conventional statistical tests.