PHARMACOKINETIC-BASED DRUG DESIGN TOOL AND METHOD

• US 20010041964A1
• Filed: 05/26/1999
• Published: 11/15/2001
• Est. Priority Date: 09/14/1998
• Status: Abandoned Application

• Current Assignee: Lion Bioscience AG (2invest AG)
• Original Assignee: Lion Bioscience AG (2invest AG)
• Inventors: SINKO, PATRICK J., NORRIS, DANIEL A., LEESMAN, GLEN D., GRASS, GEORGE M., WEHRLI, JOHN E.
• Application Number:
  US09/320,372
• Publication Number:
  US 20010041964A1
• Time in Patent Office: Days
• US Class Current: 702/19
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: G16B 35/00 ICT specially adapted for in silico combinatorial libraries of nucleic acids, proteins or peptides
• CPC Class Codes: G16C 20/60 In silico combinatorial chemistry
• CPC Class Codes: G16C 20/62 Design of libraries
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

The present invention relates to a pharmacokinetic-based design and selection tool (PK tool) and methods for predicting absorption of an administered compound of interest. The methods utilize the tool, and optionally a separately operable component or subsystem thereof. The PK tool includes as computer-readable components: (1) input/output system; (2) physiologic-based simulation model of one or more segments of a mammalian system of interest having one or more physiological barriers to absorption that is based on the selected route of administration; and (3) simulation engine having a differential equation solver. The invention also provides methods for optimizing as well as enabling minimal input requirements a physiologic-based simulation model for predicting in vivo absorption, and optionally one or more additional properties, from either in vitro or in vivo data. The PK tool of the invention may be provided as a computer system, as an article of manufacture in the form of a computer-readable medium, or a computer program product and the like. Subsystems and individual components of the PK tool also can be utilized and adapted in a variety of disparate applications for predicting the fate of an administered compound. The PK tool and methods of the invention can be used to screen and design compound libraries, select and design drugs, as well as predict drug efficacy in mammals from in vitro and/or in vivo data of one or more compounds of interest. The PK tool and methods of the invention also finds use in selecting, designing, and preparing drug compounds, and multi-compound drugs and drug formulations (i.e., drug delivery system) for preparation of medicaments for use in treating mammalian disorders.

Claims

1. An article of manufacture comprising a computer readable medium having computer readable program code embodied therein for simulating absorption of a compound in a mammal of interest, and having computer readable input/output system, computer readable simulation engine, and computer readable simulation model of one or more segments of a selected mammalian system having one or more physiological barriers to absorption of said compound based on a selected route of administration, said computer readable simulation model comprising as operably linked components:

(i) differential equations for one or more of fluid transit, fluid absorption, mass transit, mass dissolution, mass solubility, and mass absorption for one or more segments of said mammalian system;

(ii) initial parameter values for said differential equations corresponding to physiological parameters and selectively optimized adjustment parameters, and optionally one or more regional correlation parameters, for one or more segments of said mammalian system; and

optionally (iii) control statement rules for one or more of transit, absorption, permeability, solubility, dissolution, and concentration for one or more segments of said mammalian system;

said computer readable input/output system, said computer readable simulation engine, and said computer readable simulation model being capable of working together to carry out the steps of;

a. receiving as input data through said computer readable input/output system, dose, permeability and solubility data for said compound for one or more segments of said mammalian system; and

b. applying said computer readable simulation engine and said computer readable simulation model to simulate absorption of said compound relative to one or more segments of said mammalian system of interest.

5. The article of manufacture of

claim 1

, wherein said simulation model corresponds to a compartment-flow model comprising compartments that are operably linked through flow regulators modified by one or more converters.

6. The article of manufacture of

claim 5

, wherein said compartments comprise one or more compartments characterized by a parameter selected from the group consisting of fluid volume, fluid absorption, formulation, insoluble mass, soluble mass, and soluble mass absorption.

7. The article of manufacture of

claim 5

, wherein said flow regulators are characterized by a parameter selected from the group consisting of fluid absorption rate, fluid transit rate, formulation transit rate, formulation release rate, insoluble mass transit rate, insoluble mass dissolution rate, soluble mass transit rate, and soluble mass absorption rate.

8. The article of manufacture of

claim 5

, wherein said converters are characterized by a parameter selected from the group consisting of fluid volume, fluid volume absorption rate constant, fluid volume transit rate constant, insoluble mass, insoluble mass transit rate constant, dissolution rate constant, soluble mass, soluble mass transit rate constant, surface area, dissolved mass concentration and permeability.

9. The article of manufacture of

claim 5

, wherein one or more of said converters are characterized by a selectively optimized adjustment parameter.

10. The article of manufacture of

claim 5

, wherein one or more of said converters are characterized by a regional correlation parameter.

11. The article of manufacture of

claim 1

, wherein said control statement rules are IF . . . THEN production rules.

12. The article of manufacture of

claim 1

, wherein said physiological parameters are characterized by a parameter selected from the group consisting of soluble mass transfer rate constant, permeability, solubility, dissolution rate, and transport mechanism.

13. The article of manufacture of

claim 1

, wherein said physiological parameters are characterized by a parameter selected from the group consisting of pH, initial fluid volume, surface area, fluid volume transit time, insoluble mass transit time, soluble mass transit time, fluid volume transfer rate, and fluid absorption rate.

14. The article of manufacture of

claim 1

, wherein said mammal is human.

15. The article of manufacture of

claim 1

, where said input data further comprises data for said compound of interest selected from the group consisting of dissolution rate, transport mechanism, transit time, pH and formulation release rate.

16. The article of manufacture of

claim 1

, wherein said input data is in vitro data.

17. The article of manufacture of

claim 16

, wherein said in vitro data is permeability data derived from an assay selected from the group consisting of a cell-based assay and a tissue-based assay.

18. The article of manufacture of

claim 16

, wherein said in vitro data is transport mechanism data derived from an assay selected from the group consisting of a cell-based assay and a tissue-based assay.

19. The article of manufacture of

claim 16

, wherein said in vitro data is permeability data derived from structure-activity relationship data of said compound.

20. The article of manufacture of

claim 16

, wherein said in vitro data is dissolution rate data derived from structure-activity relationship data of said compound.

21. The article of manufacture of

claim 16

, wherein said in vitro data is solubility data derived from structure-activity relationship data of said compound.

2. The article of manufacture of claim I, wherein said mammalian system is selected from the group consisting of the gastrointestinal tract, the eye, the nose, the lung, the skin, and the brain.

3. The article of manufacture of

claim 2

, wherein said mammalian system is the gastrointestinal tract.

4. The article of manufacture of

claim 3

, wherein said segments are selected from the group consisting of stomach, duodenum, jejunum, ileum, and colon.

22. A computer program product for simulating absorption of a compound in a mammal, and having computer readable program code input/output system, computer readable program code simulation engine, and computer readable program code simulation model of one or more segments of a selected mammalian system having one or more physiological barriers to absorption based on a selected route of administration, said computer readable program code simulation model comprising as operably linked components:

(i) differential equations for one or more of fluid transit, fluid absorption, mass transit, mass dissolution, mass solubility, and mass absorption for one or more segments of said mammalian system;

(ii) initial parameter values for said differential equations corresponding to physiological parameters and selectively optimized adjustment parameters, and optionally regional correlation parameters, for one or more segments of said mammalian system; and

(iii) control statement rules for one or more of transit, absorption, permeability, solubility, dissolution, and concentration for one or more segments of said mammalian system;

wherein said computer readable program code input/output system, said computer readable program code simulation engine, and said computer readable program code simulation model being capable of working together to carry out the steps of;

a. receiving as input data through said computer readable program code input/output system, dose, permeability and solubility data for said compound for one or more segments of said mammalian system; and

b. applying said computer readable program code simulation engine and said computer readable program code simulation model to simulate absorption of said compound relative to one or more segments of said mammalian system.

23. An article of manufacture comprising a computer readable medium having computer readable program code embodied therein for simulating a pharmacokinetic property of a compound in a mammal of interest, and having computer readable input/output system, computer readable simulation engine, and computer readable physiologic pharmacokinetic simulation model of one or more anatomical segments of a selected mammalian system, said computer readable physiologic pharmacokinetic simulation model comprising differential equations for calculating as a function of time the change in (i) a physiological parameter of one or more of said segments and (ii) a pharmacokinetic property comprising an absorption parameter of a compound relative to a selected route of administration, barrier to absorption and sampling site of one or more of said segments, wherein one or more of said differential equations is modified by a selectively optimized adjustment parameter;

said computer readable input/output system, said computer readable simulation engine, and said computer readable physiologic pharmacokinetic simulation model being capable of working together to carry out the steps of;

a. receiving through said computer readable input/output system input data comprising dose, permeability and solubility data for said compound for one or more segments of said mammalian system of interest; and

b. applying said computer readable simulation engine and said computer readable physiologic pharmacokinetic simulation model to simulate a pharmacokinetic property of said compound relative to one or more segments of said mammalian system of interest.

24. The article of manufacture of

claim 23

, wherein said differential equations are for one or more of fluid transit, fluid absorption, mass transit, mass dissolution, mass solubility, and mass absorption for one or more segments of said mammalian system.

25. The article of manufacture of

claim 23

, wherein said differential equations comprise initial parameter values corresponding to said physiological parameter and said selectively optimized adjustment parameter for one or more segments of said mammalian system.

26. The article of manufacture of

claim 23

, wherein said physiologic pharmacokinetic simulation model comprises control statement rules for one or more of transit, absorption, permeability, solubility, dissolution, and concentration for one or more segments of said mammalian system.

27. The article of manufacture of

claim 26

, wherein said control statement rules are IF . . . THEN production rules.

28. The article of manufacture of

claim 23

, wherein said input/output system comprises a user interface.

29. The article of manufacture of

claim 23

, wherein said simulation engine comprises a differential equation solver.

30. The article of manufacture of

claim 23

, wherein said pharmacokinetic property is selected from the group consisting of absorption, distribution, metabolism, elimination and toxicity.

31. The article of manufacture of

claim 23

, wherein said absorption parameter is selected from the group consisting of concentration, permeability, solubility, dissolution rate, transport mechanism, and formulation release rate.

32. The article of manufacture of

claim 23

, wherein said physiological parameter is selected from the group consisting of pH, fluid volume, fluid volume transfer rate, fluid absorption, surface area, and transit time.

33. The article of manufacture of

claim 23

, wherein said mammalian system of interest is human.

34. The article of manufacture of

claim 23

, wherein said mammalian system of interest is selected from the group consisting of gastrointestinal tract, liver, heart, kidney, eye, nose, lung, skin and brain.

35. The article of manufacture of

claim 34

, wherein said mammalian system of interest is gastrointestinal tract and said segments are selected from the group consisting of stomach, duodenum, jejunum, ileum and colon.

36. The article of manufacture of

claim 23

, wherein said input data includes data selected from the group consisting of dissolution rate, transport mechanism and formulation release rate.

37. The article of manufacture of

claim 23

, wherein said differential equations comprise one or more input variables corresponding to said input data for calculating as one or more output variables said change in said physiological parameter.

38. The article of manufacture of

claim 23

, wherein said differential equations comprise one or more input variables corresponding to said input data for calculating as one or more output variables said change in said absorption parameter.

39. The article of manufacture of

claim 23

, wherein said selectively optimized adjustment parameter correlates said input data to output data comprising said pharmacokinetic property of said compound.

40. The article of manufacture of

claim 39

, wherein said input data comprises in vitro data and said selectively optimized adjustment parameter comprises a best fit value obtained by (i) assigning an initial value to a selected adjustment parameter of said simulation model, (ii) fitting a combination of in vitro data and in vivo data for different compounds of a compound test set with said simulation model, (iii) selecting a best fit value for said selected adjustment parameter that, when assigned as an initial value to said selected adjustment parameter, permits said simulation model to predict said pharmacokinetic property of said compound when said input data comprises said in vitro data, and (iv) assigning said best fit value as a constant to said selected adjustment parameter so as to generate said selectively optimized adjustment parameter that modifies one or more of said differential equations.

41. The article of manufacture of

claim 40

, wherein said in vitro data is obtained from testing of a compound in one or more assays that generate data selected from the group consisting of cell, tissue, structure-activity relationship (SAR), and quantitative structure-activity relationship (QSAR) data.

42. The article of manufacture of

claim 40

, wherein said different compounds of a compound test set comprise compounds having diverse pharmacokinetic properties in said mammalian system of interest.

43. The article of manufacture of

claim 39

, wherein said input data comprises in vivo data from a first species of mammal and said mammalian system of interest comprises a second species of mammal, and wherein said selectively optimized adjustment parameter comprises a best fit value obtained by (i) assigning an initial value to a selected adjustment parameter of said simulation model, (ii) fitting a combination of in vivo data with said simulation model, said combination of in vivo data derived from testing of different compounds of a compound test set in said first species of mammal and said second species of mammal, (iii) selecting a best fit value for said selected adjustment parameter that, when assigned as an initial value to said selected adjustment parameter, permits said simulation model to predict said pharmacokinetic property of said compound when said input data comprises said in vitro data from said first species of mammal, and (iv) assigning said best fit value as a constant to said selected adjustment parameter so as to generate said selectively optimized adjustment parameter that modifies one or more of said differential equations.

44. The article of manufacture of

claim 43

, wherein said different compounds of a compound test set comprise compounds having diverse pharmacokinetic properties in said mammalian system of interest.

45. The article of manufacture of

claim 23

, wherein said selectively optimized adjustment parameter is for one or more of fluid absorption, flux, permeability, transport mechanism, transfer rate, and segment surface area.

46. The article of manufacture of

claim 23

, wherein said computer readable physiologic pharmacokinetic simulation model comprises at least two of said anatomical segments and a logic function module comprising a regional correlation estimation function and a control statement for initiating said function, wherein said estimation function when initiated is capable of generating an estimated value for a selected pharmacokinetic property of said compound in a first anatomical segment when supplied with an input value corresponding to said selected pharmacokinetic property in a second anatomical segment and with a regional correlation coefficient for said selected pharmacokinetic property of said first and second anatomical segments.

47. A computer program product for simulating a pharmacokinetic property of a compound in a mammal of interest, and having computer readable program code input/output system, computer readable program code simulation engine, and computer readable program code physiologic pharmacokinetic simulation model of one or more anatomical segments of a selected mammalian system, said computer readable program code physiologic pharmacokinetic simulation model comprising differential equations for calculating as a function of time the change in (i) a physiological parameter of one or more of said segments and (ii) a pharmacokinetic property comprising an absorption parameter of a compound relative to a selected route of administration, barrier to absorption and sampling site of one or more of said segments, wherein one or more of said differential equations is modified by a selectively optimized adjustment parameter;

said computer readable program code input/output system, said computer readable program code simulation engine, and said computer readable program code physiologic pharmacokinetic simulation model being capable of working together to carry out the steps of;

a. receiving through said computer readable program code input/output system input data comprising dose, permeability and solubility data for said compound for one or more segments of said mammalian system of interest; and

b. applying said computer readable program code simulation engine and said computer readable program code physiologic pharmacokinetic simulation model to simulate a pharmacokinetic property comprising an absorption parameter of said compound relative to one or more segments of said mammalian system of interest.

48. The article of manufacture of

claim 47

, wherein said computer readable program code physiologic pharmacokinetic simulation model comprises at least two of said anatomical segments and a logic function model comprising a regional correlation estimation function and a control statement for initiating said function, wherein said estimation function when initiated is capable of generating an estimated value for a selected pharmacokinetic property of said compound in a first anatomical segment when supplied with an input value corresponding to said selected pharmacokinetic property in a second anatomical segment and with a regional correlation coefficient for said selected pharmacokinetic property of said first and second anatomical segments.

49. An article of manufacture comprising a computer readable medium having computer readable program code embodied therein for simulating a pharmacokinetic property of a compound in a mammal of interest, and having computer readable input/output system, computer readable simulation engine, and computer readable physiologic pharmacokinetic simulation model of at least two segments of a selected mammalian system of interest, said computer readable physiologic pharmacokinetic simulation model comprising as operably linked components:

(i) differential equations for calculating the change in one or more physiological parameters of first and second segments of said mammalian system of interest and the movement and disposition of said compound in said first and second segments as a function of time, and (ii) a logic function module having a regional correlation parameter estimation function and a control statement for initiating said function, wherein said estimation function when initiated is capable of generating an estimated value for a selected pharmacokinetic property comprising an absorption parameter of said compound in said first segment when supplied with an input value corresponding to said selected pharmacokinetic property of said compound in said second segment and with a regional correlation coefficient for said selected pharmacokinetic parameter of said first and second segments;

said computer readable input/output system, said computer readable simulation engine, and said computer readable physiologic pharmacokinetic simulation model being capable of working together to carry out the steps of;

a. receiving through said computer readable input/output system input data comprising a pharmacokinetic property of said compound in said second segment of said mammalian system of interest; and

b. applying said computer readable simulation engine and said computer readable physiologic pharmacokinetic simulation model to initiate said estimation function to estimate said pharmacokinetic property of said compound in said first segment of said mammalian system of interest.

50. The article of manufacture of

claim 49

, wherein said regional correlation estimation function comprises a function/transformation algorithm.

51. The article of manufacture of

claim 50

, wherein said fiction/transformation algorithm is selected from the group consisting of a polynomial, exponential, and logarithm.

52. The article of manufacture of

claim 49

, wherein said regional correlation coefficient comprises a best fit value that transforms said input data comprising said pharmacokinetic property of said compound in said second segment to an estimated pharmacokinetic property of said compound in said first segment.

53. The article of manufacture of

claim 49

, wherein said pharmacokinetic property is selected from the group consisting of absorption, distribution, metabolism, elimination and toxicity.

54. The article of manufacture of

claim 49

, wherein said pharmacokinetic parameter is selected from the group consisting of permeability, solubility, dissolution rate and transport mechanism.

55. The article of manufacture of

claim 49

, wherein said differential equations are selected from the group consisting of equations for fluid transit, fluid absorption, mass transit, mass dissolution, mass solubility, and mass absorption.

56. The article of manufacture of

claim 49

, wherein said mammalian system of interest is selected from the group consisting of gastrointestinal tract, liver, heart, kidney, eye, nose, lung, skin and brain.

57. The article of manufacture of

claim 49

, wherein said mammalian system of interest is human.

58. The article of manufacture of

claim 49

, wherein said input data comprises in vitro data.

59. The article of manufacture of

claim 58

, wherein said in vitro data is derived from testing of said compound in an assay that generates data selected from the group consisting of cell, tissue, physicochemical, structure-activity relationship (SAR) SAR, and quantitative structure-activity relationship (QSAR) QSAR data.

60. The article of manufacture of

claim 49

, wherein one or more of said differential equations is modified by a selectively optimized adjustment parameter.

61. A computer program product for simulating a pharmacokinetic property of a compound in a mammal of interest, and having computer readable program code input/output system, computer readable program code simulation engine, and computer readable program code physiologic pharmacokinetic simulation model of at least two segments of a selected mammalian system of interest, said computer readable program code physiologic pharmacokinetic simulation model comprising as operably linked components:

(i) differential equations for calculating the change in one or more physiological parameters of first and second segments of said mammalian system of interest and the movement and disposition of said compound in said first and second segments as a function of time, and (ii) a logic function module having a regional correlation parameter estimation function and a control statement for initiating said function, wherein said estimation function when initiated is capable of generating an estimated value for a selected pharmacokinetic property comprising an absorption parameter of said compound in said first segment when supplied with an input value corresponding to said selected pharmacokinetic property of said compound in said second segment and with a regional correlation coefficient for said selected pharmacokinetic parameter of said first and second segments;

said computer readable program code input/output system, said computer readable program code simulation engine, and said computer readable program code physiologic pharmacokinetic simulation model being capable of working together to carry out the steps of;

a. receiving through said computer readable program code input/output system input data comprising a pharmacokinetic property of said compound in said second segment of said mammalian system of interest; and

b. applying said computer readable program code simulation engine and said computer readable program code physiologic pharmacokinetic simulation model to initiate said estimation function to estimate said pharmacokinetic property of said compound in said first segment of said mammalian system of interest.

62. The computer program product of

claim 61

, wherein one or more of said differential equations is modified by a selectively optimized adjustment parameter.

63. An article of manufacture comprising a computer readable medium having embodied therein a computer readable physiologic pharmacokinetic simulation model of one or more anatomical segments of a selected mammalian system, said computer readable physiologic pharmacokinetic simulation model comprising differential equations for calculating as a function of time the change in (i) a physiological parameter of one or more of said segments and (ii) a pharmacokinetic property comprising an absorption parameter of a compound relative to a selected route of administration, barrier to absorption and sampling site of one or more of said segments, wherein one or more of said differential equations is modified by a selectively optimized adjustment parameter.

64. An article of manufacture comprising a computer readable medium having embodied therein a computer readable physiologic pharmacokinetic simulation model of at least two segments of a selected mammalian system of interest, said computer readable physiologic pharmacokinetic simulation model comprising as operably linked components:

(i) differential equations for calculating the change in one or more physiological parameters of first and second segments of said mammalian system of interest and the movement and disposition of said compound in said first and second segments as a function of time, and (ii) a logic function module having a regional correlation parameter estimation function and a control statement for initiating said function, wherein said estimation function when initiated is capable of generating an estimated value for a selected pharmacokinetic property comprising an absorption parameter of said compound in said first segment when supplied with an input value corresponding to said selected pharmacokinetic property of said compound in said second segment and with a regional correlation coefficient for said selected pharmacokinetic parameter of said first and second segments.