MULTIPLE COMPARTMENT DOSING MODEL

• US 20100106473A1
• Filed: 10/23/2009
• Published: 04/29/2010
• Est. Priority Date: 10/24/2008
• Status: Active Grant

• Current Assignee: Amicus Therapeutics, Inc.
• Original Assignee: Amicus Therapeutics, Inc.
• Inventors: Lockhart, Daniel J., Lockhart, David J.
• Granted Patent: US 8,321,148 B2
• Time in Patent Office: Days
• US Class Current: 703/2
• CPC Class Codes: G16B 5/00 ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
• CPC Class Codes: G16B 5/30 Dynamic-time models

Abstract

The method for modeling a dosing regimen for a medicament includes providing a system having at least two biocompartments. The method determines steady state levels in each of the biocompartments. After that, the method provides for modifying values to calculate an amount of at least one protein in one of the biocompartments to which the protein is being transported. Next, the method calculates and integrates a weighted value of the protein to find a weighted area under the curve. Then, the method calculates and integrates a non-drug value of the protein to find a non-drug area under the curve. Finally, the method evaluates one or more dosing regimens by comparing the weighted area under the curve and the non-drug area under the curve of the protein to determine a net effect of the drug over the time period.

Claims

1. A method for modeling a dosing regimen for a medicament comprising:

providing a system including;

at least two biocompartments selected from the group consisting of intracellular and extracellular regions;

determining steady state levels in each of said at least two biocompartments by assigning variables to represent a protein production rate in one of said at least two biocompartments, a degradation rate constant for each of said at least two biocompartments, and a transport rate constant between said at least two biocompartments using a set of equations;

modifying values of said assigned variables in said set of equations to use said set of equations to calculate an amount of at least one protein in one of said at least two biocompartments to which said at least one protein is being transported, as a function of time, said set of equations reflect selected characteristics of said at least one protein and one or more drug pulse parameters, said one or more drug pulse parameters include a start time, a duration, an interval time, a number of pulses, an amount of drug, and a number of times the settings are repeated;

calculating a weighted value of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported, wherein said weighted value is the result of multiplying a calculated factor by an amount of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported by, said calculated factor being determined using a drug concentration pulse curve and a set of input parameters including a substrate concentration, a maximum drug concentration, a rise time, and a drug elimination half-life;

integrating said weighted value over a time period to find a weighted area under the curve;

calculating a non-drug value of said at least one protein in said one of said at two biocompartments to which said at least one protein is being transported, wherein said non-drug value is an amount of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported without the addition of a drug;

integrating said non-drug value over said time period to find a non-drug area under the curve; and

evaluating one or more dosing regimens by comparing said weighted area under the curve and said non-drug area under the curve of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported over said time period to determine a net effect of said drug over said time period.

2. The method of claim 1, wherein said weighted values of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported is graphically displayed using one or more of the following including a line graph and a bar chart.

3. The method of claim 1, wherein said protein production rate is graphically displayed using one or more of the following including a line graph and a bar chart.

4. The method of claim 3, wherein said graphically displayed protein production rate shows said protein production rate in each of said at least two biocompartments being run to steady state levels.

5. The method of claim 1, wherein a drug pulse concentration curve is graphically displayed based on said one or more drug pulse parameters.

6. The method of claim 1, wherein said at least one protein comprises an enzyme.

7. The method of claim 6, wherein said enzyme is coupled to a substrate to form a pair.

8. The method of claim 7, wherein said pair may be selected from the group consisting of the following:

said enzyme alpha galactosidase A and said substrate globotriaosylceramide;

said enzyme glucocerebrosidase and said substrate glucocerebroside; and

said enzyme acid maltase and said substrate glycogen.

9. The method of claim 1, wherein said one or more drug pulse parameters further include an ERT enzyme, said ERT enzyme being added to said one of said at least two biocompartments to which said at least one protein is being transported at an ERT interval time.

28. The method of claim 1, wherein said one or more drug pulse parameters further include an ERT enzyme, said ERT enzyme being added to said one of said at least two biocompartments to which said at least one protein is being transported at an ERT interval time.

10. A system for modeling a dosing regimen of a medicament comprising:

a display device;

a data store comprising a plurality of values for modeling a dosing regime of a medicament; and

a service delivery device operatively connected to said display device and said data store, said service delivery device including a processor and a memory for storing instructions that, in response to receiving a request to model the dosing regimen of a medicament, causes the processor to;

provide a system including;

at least two biocompartments selected from the group consisting of intracellular and extracellular regions;

determine steady state levels in each of said at least two biocompartments by assigning variables to represent a protein production rate in one of said at least two biocompartments, a degradation rate constant for each of said at least two biocompartments, and a transport rate constant between said at least two biocompartments using a set of equations;

modify values of said assigned variables in said set of equations to use said set of equations to calculate an amount of at least one protein in one of said at least two biocompartments to which said at least one protein is being transported, as a function of time, said set of equations reflect selected characteristics of said at least one protein and one or more drug pulse parameters, said one or more drug pulse parameters include a start time, a duration, an interval time, a number of pulses, an amount of drug, and a number of times the settings are repeated;

calculate a weighted value of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported, wherein said weighted value is the result of multiplying a calculated factor by an amount of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported by, said calculated factor being determined using a drug concentration pulse curve and a set of input parameters including a substrate concentration, a maximum drug concentration, a rise time, and a drug elimination half-life;

integrate said weighted value over a time period to find a weighted area under the curve;

calculate a non-drug value of said at least one protein in said one of said at two biocompartments to which said at least one protein is being transported, wherein said non-drug value is an amount of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported without the addition of a drug;

integrate said non-drug value over said time period to find a non-drug area under the curve; and

evaluate one or more dosing regimens by comparing said weighted area under the curve and said non-drug area under the curve of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported over said time period to determine a net effect of said drug over said time period.

11. The system of claim 10, wherein the memory stores instructions that, in response to receiving the request, cause the processor to graphically display said weighted values of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported using one or more of the following including a line graph and a bar chart.

12. The system of claim 10, wherein the memory stores instructions that, in response to receiving the request, cause the processor to graphically display said protein production rate using one or more of the following including a line graph and a bar chart.

13. The system of claim 10, wherein the memory stores instructions that, in response to receiving the request, cause the processor to graphically display said protein production rate of each of said at least two biocompartments being run to steady state levels.

14. The system of claim 10, wherein the memory stores instructions that, in response to receiving the request, cause the processor to graphically display a drug pulse concentration curve based on said one or more drug pulse parameters.

15. The system of claim 10, wherein the memory stores instructions that, in response to receiving the request, cause the processor to graphically display the amount of said at least one protein using one or more of the following including a line graph and a bar chart.

16. The system of claim 10, wherein said at least one protein comprises an enzyme.

17. The system of claim 16, wherein said enzyme is coupled to a substrate to form a pair.

18. The system of claim 17, wherein said pair may be selected from the group consisting of the following:

said enzyme alpha galactosidase A and said substrate globotriaosylceramide;

said enzyme glucocerebrosidase and said substrate glucocerebroside; and

said enzyme acid maltase and said substrate glycogen.

19. The system of claim 10, wherein said one or more drug pulse parameters further include an ERT enzyme, said ERT enzyme being added to said one of said at least two biocompartments to which said at least one protein is being transported at an ERT interval time.

20. A computer-implemented method for modeling a dosing regimen for a medicament comprising:

providing a system including;

at least two biocompartments selected from the group consisting of intracellular and extracellular regions;

determining steady state levels in each of said at least two biocompartments by assigning variables to represent a protein production rate in one of said at least two biocompartments, a degradation rate constant for each of said at least two biocompartments, and a transport rate constant between said at least two biocompartments using a set of equations;

modifying values of said assigned variables in said set of equations to use said set of equations to calculate an amount of at least one protein in one of said at least two biocompartments to which said at least one protein is being transported, as a function of time, said set of equations reflect selected characteristics of said at least one protein and one or more drug pulse parameters, said one or more drug pulse parameters include a start time, a duration, an interval time, a number of pulses, an amount of drug, and a number of times the settings are repeated;

calculating a weighted value of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported, wherein said weighted value is the result of multiplying a calculated factor by an amount of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported, said calculated factor being determined using a drug concentration pulse curve and a set of input parameters including a substrate concentration, a maximum drug concentration, a rise time, and a drug elimination half-life;

integrating said weighted value over a time period to find a weighted area under the curve;

calculating a non-drug value of said at least one protein in said one of said at two biocompartments to which said at least one protein is being transported, wherein said non-drug value is an amount of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported without the addition of a drug;

integrating said non-drug value over said time period to find a non-drug area under the curve; and

evaluating one or more dosing regimens by comparing said weighted area under the curve and said non-drug area under the curve of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported over said time period to determine a net effect of said drug over said time period.

21. The computer-implemented method of claim 20, wherein said weighted values of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported is graphically displayed using one or more of the following including a line graph and a bar chart.

22. The computer-implemented method of claim 20, wherein said protein production rate is graphically displayed using one or more of the following including a line graph and a bar chart.

23. The computer-implemented method of claim 20, wherein said graphically displayed protein production rate shows said protein production rate in each of said at least two biocompartments being run to steady state levels.

24. The computer-implemented method of claim 20, wherein a drug pulse concentration curve is graphically displayed based on said one or more drug pulse parameters.

25. The computer-implemented method of claim 20, wherein said at least one protein comprises an enzyme.

26. The computer-implemented method of claim 25, wherein said enzyme is coupled to a substrate to form a pair.

27. The computer-implemented method of claim 26, wherein said pair may be selected from the group consisting of the following:

said enzyme alpha galactosidase A and said substrate globotriaosylceramide;

said enzyme glucocerebrosidase and said substrate glucocerebroside; and

said enzyme acid maltase and said substrate glycogen.

29. A computer-readable medium for modeling a dosing regimen for a medicament comprising instructions executable by a computing device that, when applied to the computing device causes the device to:

provide a system including;

at least two biocompartments selected from the group consisting of intracellular and extracellular regions;

determine steady state levels in each of said at least two biocompartments by assigning variables to represent a protein production rate in one of said at least two biocompartments, a degradation rate constant for each of said at least two biocompartments, and a transport rate constant between said at least two biocompartments using a set of equations;

modify values of said assigned variables in said set of equations to use said set of equations to calculate an amount of at least one protein in one of said at least two biocompartments to which said at least one protein is being transported, as a function of time, said set of equations reflect selected characteristics of said at least one protein and one or more drug pulse parameters, said one or more drug pulse parameters include a start time, a duration, an interval time, a number of pulses, an amount of drug, and a number of times the settings are repeated;

calculate a weighted value of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported, wherein said weighted value is the result of multiplying a calculated factor by an amount of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported, said calculated factor being determined using a drug concentration pulse curve and a set of input parameters including a substrate concentration, a maximum drug concentration, a rise time, and a drug elimination half-life;

integrate said weighted value over a time period to find a weighted area under the curve;

calculate a non-drug value of said at least one protein in said one of said at two biocompartments to which said at least one protein is being transported, wherein said non-drug value is an amount of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported without the addition of a drug;

integrate said non-drug value over said time period to find a non-drug area under the curve; and

evaluate one or more dosing regimens by comparing said weighted area under the curve and said non-drug area under the curve of said at least one protein in said one of said at least two biocompartments to which said at least one protein is being transported over said time period to determine a net effect of said drug over said time period.