Multi-drug titration and evaluation

• US 20040132633A1
• Filed: 02/02/2004
• Published: 07/08/2004
• Est. Priority Date: 02/13/2002
• Status: Active Grant

• Current Assignee: Virginia Commonwealth University
• Original Assignee: Virginia Commonwealth University
• Inventors: Shih, Margaret, Chinchili, Vernon M, Carter, W Hans Jr., Gennings, Chris
• Granted Patent: US 7,610,153 B2
• Time in Patent Office: Days
• US Class Current: 514/1
• CPC Class Codes: G16H 10/20 for electronic clinical trials or questionnaires
• CPC Class Codes: G16H 20/10 relating to drugs or medications, e.g. for ensuring correct administration to patients

Abstract

Titration of a combination of drugs or treatment modalities within individual subjects is carried out using an evolutionary operation (EVOP) direct-search procedure such as the Nelder-Mead simplex. Desirability functions are incorporated to define the main response of interest and additional responses or constraints. Statistical methodology for determining whether the titrated treatment combination has resulted in an improvement in patient response and for evaluating whether a therapeutic synergism exists is also incorporated. Inferences can be made about the efficacy of the combination or about the individual drugs or treatment modalities that comprise the combination. This approach allows every patient the potential to benefit from the combination under study and permits the consideration of multiple endpoints simultaneously.

Claims

1. A method for titrating a multi-modality therapy regimen in at least one subject, comprising the steps of:

providing n modalities to said subject in a plurality of dose combinations;

measuring one or more clinical endpoints in said subject;

assigning measurements made in said measuring step for each of said one or more clinical endpoints to a desirability function;

combining all desirability functions to obtain a composite desirability function for each of said plurality of dose combinations;

associating each composite desirability function with a vertex of a geometric figure, wherein said geometric figure has vertices, the number of which is equal to a number of said plurality of dose combinations;

determining a next dose combination by applying an evolutionary operation direct search algorithm to said geometric figure, wherein said next dose combination is generated by the evolutionary operation direct search algorithm moving away from a vertex which represents a least desirable dose combination through dose space to a new location, wherein said new location represents said next dose combination, and

performing each of said steps multiple times, wherein said step of performing each of said steps constitutes titration of said multi-modality therapy regimen.

2. The method of claim 1 wherein said evolutionary operational direct search algorithm is the Nelder-Mead algorithm, said geometric figure is a simplex, and said number of said plurality of dose combinations is p+1.

3. The method of claim 1 wherein said multi-modality therapy regimen is used to treat a combined modality therapy-requiring, disease or condition selected from the group consisting of cancer, diabetes, asthma, AIDS, and hypertension.

4. The method of claim 1 wherein said dose combination comprises at least one exposure to radiation.

5. The method of claim 1 wherein said dose combination comprises at least one exercise regimen.

6. The method of claim 1 wherein said desirability function is generated from a logistic cumulative distribution function.

7. The method of claim 1 wherein said composite desirability function is unweighted.

8. The method of claim 1 wherein said composite desirability function is weighted.

9. The method of claim 1 wherein said at least one subject is one subject.

10. The method of claim 1 wherein said at least one subject is a plurality of subjects.

11. A computerized system for titrating a multi-modality treatment regimen in a subject, comprising

means for entering into a computer a number n of modalities to be used in the treatment regimen;

means for generating a geometric figure having vertices, wherein each of said vertices represents one of a plurality of dose combinations;

means for determining a composite desirability function for each of said dose combinations and associating said composite desirability function with one of said vertices in said geometric figure;

means for applying an evolutionary operational algorithm to each of said composite desirability functions; and

,

means for outputting a next dose combination based on a lowest composite desirability function of said composite desirability functions determined by said means for applying.

12. A method for titrating a multi-modality therapy regimen in a subject, comprising the steps of:

providing n modalities to said subject in a plurality of dose combinations;

measuring a clinical endpoint in said subject;

associating measurements made in said measuring step for said clinical endpoint with a vertex of a geometric figure, wherein said geometric figure has vertices, the number of which is equal to a number of said plurality of dose combinations; and

determining a next dose combination by applying an evolutionary operation direct search algorithm to said geometric figure, wherein said next dose combination is generated by the evolutionary operation direct search algorithm moving away from a vertex which represents a least desirable dose combination through dose space to a new location, wherein said new location represents said next dose combination, and

performing each of said steps multiple times, wherein said step of performing each of said steps constitutes titration of said multi-modality therapy regimen.

13. The method of claim 12 further comprising the step of assigning said measurements obtained in said measuring step to a desirability function prior to associating said measurements with a vertex of said geometric figure.