Individualization of therapy with anesthetics

• US 20040101477A1
• Filed: 11/27/2002
• Published: 05/27/2004
• Est. Priority Date: 11/27/2002
• Status: Abandoned Application

• Current Assignee: Xanthus Life Sciences, Inc. (Sarossa Plc)
• Original Assignee: Xanthus Life Sciences, Inc. (Sarossa Plc)
• Inventors: Leyland-Jones, Brian
• Application Number:
  US10/307,210
• Publication Number:
  US 20040101477A1
• Time in Patent Office: Days
• US Class Current: 424/9.2
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: B82Y 30/00 Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: G01N 33/5308 for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites

Abstract

The invention relates to the individualization of therapy on the basis of a phenotypic profile of an individual. More specifically, the present invention relates to the use of metabolic phenotyping for the individualization of treatment with anesthetics.

Claims

1. A method of characterizing a multi-determinant metabolic phenotype for at least one anesthetic, wherein a plurality of phenotypic determinants are identified as corresponding to respective metabolic characteristics;

said method comprising;

a) administering to an individual a probe substrate specific to metabolic pathway(s) for said at least one anesthetic;

b) detecting metabolites of said metabolic pathway(s) in a biological sample from said individual in response to said probe substrate; and

c) characterizing respective phenotypic determinants of said multi-determinant metabolic phenotype based on detected metabolites.

2. The method of claim 1, wherein said at least one anesthetic is selected from the group consisting of local and general anesthetics.

3. The method of claim 1, wherein said at least one anesthetic is halothane.

4. The method of claim 1 which further comprises a step i) after step b):

i) quantifying a ratio of respective detected metabolites for each of said metabolic pathways in said biological sample.

5. The method of claim 4, wherein said ratio is selected from the group consisting of concentration ratio, molar ratio, chiral ratio, ratio of area under the curve and signal peak height ratio.

6. The method of claim 1, wherein said probe substrate is at least one probe substrate known to be metabolized by said metabolic pathway.

7. The method of claim 1, wherein said probe substrate is other than an inducer or inhibitor of said metabolic pathway.

8. The method of claim 1, wherein said step b) or step c) is effected using an affinity complexation agent specific to each of said metabolites.

9. The method of claim 8, wherein said affinity complexation agent is an antibody.

10. The method of claim 9, wherein said antibody is a monoclonal antibody.

11. The method of claim 9, wherein said antibody is a polyclonal antibody.

12. The method of claim 8, wherein said affinity complexation agent is a molecular imprinted polymer.

13. The method of claim 8, wherein said affinity complexation agent is an aptmer.

14. The method of claim 8, wherein said affinity complexation agent is a receptor.

15. The method of claim 8, wherein said affinity complexation agent is an anticalin.

16. The method of claim 1, further comprising a ligand binding assay.

17. The method of claim 16, wherein said ligand binding assay is selected from the group consisting of immunoassay, enzyme-linked immunosorbent assay (ELISA), microarray formatted immunoassay and microarray formatted ELISA.

18. The method of claim 16, wherein said ligand binding assay is a rapid immunoassay (Dipstick assay).

19. The method of claim 18, wherein said rapid immunoassay is based on Rapid Analyte Measurement Platform (RAMP) technology.

20. The method of claim 18, wherein said rapid immunoassay is based on light-emitting immunoassay technology.

21. The method of claim 16, wherein said ligand binding assay is performed with a biosensor.

22. The method of claim 21, wherein said biosensor is an immunosensor.

23. The method of claim 21 wherein wherein the means of detection of said biosensor is an electrochemical sensor.

24. The method of claim 21, wherein the means of detection of said biosensor is an optical sensor.

25. The method of claim 21, wherein the means of detection of said biosensor is a microgravimetric sensor.

26. The method of claim 25, wherein said microgravimetric sensor is a quartz crystal microbalance (QCM).

27. The method of claim 1, wherein step b) is effected by using a qualitative detection instrument.

28. The method according to claim 1, wherein each of said plurality of phenotypic determinants of said multi-determinant metabolic phenotype is an enzyme-specific determinant.

29. The method according to claim 1, wherein said multi-determinant metabolic phenotype is comprised of at least one determinant indicative of an individual'"'"'s metabolic capacity for at least one drug metabolizing enzyme.

30. The method of claim 29, wherein said at least one drug metabolizing enzyme is CYP2E1.

31. The method of claim 30, further comprising at least one drug metabolizing enzyme selected from the group consisting of N-acetyltransferase-1 (NAT-1), N-acetyltransferase-2 (NAT-2), CYP1A2, CYP2D6, CYP2A6, CYP3A4, CYP2C9, CYP2C19, UGTs, GSTs, and STs.

32. The method of claim 1, wherein step a) is effected by using a plurality of probe substrates and wherein each probe substrate is specific to at least one metabolic pathway of interest.

33. The method of claim 1, further comprising:

d) measuring at least one determinant for drug clearance known to affect the toxicity or efficacy of said at least one anesthetic compound;

wherein said at least one determinant is factored together with at least rate of probe substrate metabolism to determine a non-toxic and effective amount of said at least one anesthetic compound to be administered to said individual.

34. The method of claim 33, wherein said at least one determinant for drug clearance is based on body surface area or hepatic enzyme levels of said individual.

35. The method of claim 1, further comprising:

d) measuring at least one determinant for drug susceptibility known to affect the toxicity or efficacy of said at least one anesthetic compound;

wherein said at least one determinant for drug susceptibility is factored together with at least rate of probe substrate metabolism to determine a non-toxic and effective amount of said at least one anesthetic compound to be administered to said individual.

36. The method of claim 35, wherein said at least one determinant for drug susceptibility is based on pretreatment renal function of said individual determined prior to step a).

37. The method of claim 35, wherein said at least one anesthetic is selected from the group consisting of local and general anesthetics.

38. The method of claim 35, wherein said at least one anesthetic is halothane.

39. The method of claim 36, further comprising:

e) measuring at least one determinant for drug susceptibility known to affect the toxicity or efficacy of said at least one anesthetic compound;

wherein said at least one determinant for drug susceptibility is factored together with at least rate of probe substrate metabolism to determine a non-toxic and effective amount of said at least one anesthetic compound to be administered to said individual.

40. The method of claim 39, wherein said at least one determinant for drug susceptibility is based on pretreatment renal function of said individual determined prior to step a).

41. The method of claim 39, wherein said at least one anesthetic is selected from the group consisting of local and general anesthetics.

42. The method of claim 39, wherein said at least one anesthetic is halothane.

90. The method of claim 4, wherein said step b) or step c) is effected using an affinity complexation agent specific to each of said metabolites.

91. The method of claim 1, wherein said step b) and step c) are effected using an affinity complexation agent specific to each of said metabolites.

92. The method of claim 4, wherein said step b) and step c) are effected using an affinity complexation agent specific to each of said metabolites.

43. A method of using a multi-determinant metabolic phenotype to individualize a treatment regimen for at least one anesthetic compound for an individual, wherein the multi-determinant metabolic phenotype of said individual is determined;

a safe and therapeutically effective dose of said at least one anesthetic compound treatment is determined and/or selected based on said multi-determinant metabolic phenotype of said individual.

44. The method of claim 43, wherein said at least one anesthetic is selected from the group consisting of local and general anesthetics.

45. The method of claim 43, wherein said at least one anesthetic is halothane.

46. The method of claim 43, wherein said multi-determinant metabolic phenotype is determined according to the method comprising:

a) administering to an individual a probe substrate specific to metabolic pathway(s) for said at least one anesthetic;

b) detecting metabolites of said metabolic pathway(s) in a biological sample from said individual in response to said probe substrate; and

c) characterizing respective phenotypic determinants of said multi-determinant metabolic phenotype based on detected metabolites.

47. A method of administering to an individual at least one anesthetic compound, said method comprising:

a) determining a multi-determinant metabolic phenotype of said individual; and

b) administering a safe and therapeutically effective dose of said at least one anesthetic compound to said individual, wherein said dose has been determined based on a metabolic profile of said individual corresponding to said individual'"'"'s metabolic phenotype for said at least one anesthetic compound as represented by said multi-determinant metabolic phenotype.

48. The method of claim 47, wherein said at least one anesthetic is selected from the group consisting of local and general anesthetics.

49. The method of claim 47, wherein said at least one anesthetic is halothane.

50. The method of claim 47, wherein said multi-determinant metabolic phenotype is characterized according to the method comprising:

a) administering to an individual a probe substrate specific to metabolic pathway(s) for said at least one anesthetic;

b) detecting metabolites of said metabolic pathway(s) in a biological sample from said individual in response to said probe substrate; and

c) characterizing respective phenotypic determinants of said multi-determinant metabolic phenotype based on detected metabolites.

51. An assay system for detecting the presence of enzyme-specific metabolites in a biological sample, said sample obtained from an individual treated with a known amount of at least one probe substrate for at least one anesthetic compound, specific for metabolic pathways of said metabolites, said assay comprising:

a) means for receiving said biological sample, including a plurality of affinity complexation agents contained therein;

b) means for detecting presence of said enzyme-specific metabolites bound to said affinity complexation agents; and

c) means for quantifying ratios of said metabolites to provide corresponding phenotypic determinants;

wherein said phenotypic determinants provide a metabolic phenotypic profile of said individual.

52. The assay system of claim 51, wherein said at least one anesthetic is selected from the group consisting of local and general anesthetics.

53. The assay system of claim 51, wherein said at least one anesthetic is halothane.

54. The assay system of claim 51, wherein said step b) or step c) is effected according to the method comprising:

a) administering to an individual a probe substrate specific to metabolic pathway(s) for said at least one anesthetic;

b) detecting metabolites of said metabolic pathway(s) in a biological sample from said individual in response to said probe substrate; and

c) characterizing respective phenotypic determinants of said multi-determinant metabolic phenotype based on detected metabolites;

wherein said probe substrate is at least one substrate known to be metabolized by said metabolic pathway, and

wherein said probe substrate is other than an inducer or inhibitor of said metabolic pathway.

55. The assay system of claim 51, wherein said assay is a ligand binding assay.

56. The assay system of claim 55, wherein said ligand binding assay is selected from the group consisting of immunoassay, enzyme-linked immunosorbent assay (ELISA), microarray formatted immunoassay and microarray formatted ELISA.

57. The assay system of claim 51, wherein said means for receiving said biological sample is a multi-well microplate including said plurality of affinity complexation agents in each well.

58. The assay system of claim 57, wherein said plurality of affinity complexation agents are bound to each well in an array-based format.

59. The assay system of claim 51, wherein said means for detecting said presence of said metabolites bound to said binding agents is a charge-coupled device (CCD) imager.

60. The assay system of claim 51, wherein said means for said quantifying ratios of said metabolites is a densitometer.

93. The assay system of claim 51, wherein said step b) and step c) are effected according to the method comprising:

a) administering to an individual a probe substrate specific to metabolic pathway(s) for said at least one anesthetic;

b) detecting metabolites of said metabolic pathway(s) in a biological sample from said individual in response to said probe substrate; and

c) characterizing respective phenotypic determinants of said multi-determinant metabolic phenotype based on detected metabolites;

wherein said probe substrate is at least one substrate known to be metabolized by said metabolic pathway, and

wherein said probe substrate is other than an inducer or inhibitor of said metabolic pathway.

61. A method of using an enzyme-specific assay for the individualization of administration of at least one anesthetic compound, which comprises:

a) conducting said assay to identify phenotypic determinants in a biological sample obtained from an individual treated with a probe substrate for said at least one anesthetic compound;

b) determining a rate of drug metabolism according to said determinants; and

c) determining and/or selecting a safe and therapeutically effective dose of said class of anesthetic compounds for said individual based on said rate.

62. The method of claim 61, wherein said assay comprises:

a) means for receiving said biological sample, including a plurality of affinity complexation agents contained therein;

b) means for detecting presence of said enzyme-specific metabolites bound to said affinity complexation agents; and

c) means for quantifying ratios of said metabolites to provide corresponding phenotypic determinants;

wherein said phenotypic determinants provide a metabolic phenotypic profile of said individual.

63. The method of claim 61, wherein said at least one anesthetic is selected from the group consisting of local and general anesthetics.

64. The method of claim 61, wherein said at least one anesthetic is halothane.

65. The method of claim 61, wherein said enzyme-specific assay is selected from the group consisting of immunoassay, enzyme-linked immunosorbent assay (ELISA), microarray formatted immunoassay and microarray formatted ELISA.

66. The method of claim 61, wherein said rate of drug metabolism corresponds to a ratio of phenotypic determinants, wherein said phenotypic determinants are enzyme-specific determinants.

67. The method of claim 66, wherein said ratio is selected from the group consisting of concentration ratio, molar ratio, chiral ratio, ratio of area under the curve and signal peak height ratio.

68. The method of claim 61, wherein said phenotypic determinants comprise phenotypic determinants for CYP2E1.

69. The method of claim 68, wherein said phenotypic determinants further comprise phenotypic determinants for any one or more of N-acetyltransferase-1 (NAT1), N-acetyltransferase-2 (NAT2), CYP1A2, CYP2A6, CYP2D6, CYP3A4, CYP2C9, and CYP2C19, UGTs, GSTs, and STs

70. A method of screening a plurality of individuals for participation in a drug treatment trial assessing the therapeutic effect of at least one anesthetic compound, said method comprising:

a) selecting individuals having a metabolic phenotype characterized as effective for metabolizing said at least one anesthetic compound.

71. The method of claim 70, wherein said at least one anesthetic is selected from the group consisting of local and general anesthetics.

72. The method of claim 70, wherein said at least one anesthetic is halothane.

73. The method of claim 70, wherein said multi-determinant metabolic phenotype is determined according to the method comprising:

a) administering to an individual a probe substrate specific to metabolic pathway(s) for said at least one anesthetic;

b) detecting metabolites of said metabolic pathway(s) in a biological sample from said individual in response to said probe substrate; and

c) characterizing respective phenotypic determinants of said multi-determinant metabolic phenotype based on detected metabolites.

74. A method of screening a plurality of individuals for treatment with at least one anesthetic compound, said method comprising:

a) genotyping said individuals to identify individuals lacking at least one allelic variation known to prompt toxicity of said at least one anesthetic compound; and

b) selecting individuals having a metabolic phenotype characterized as effective for metabolizing said at least one anesthetic compound.

75. The method of claim 74, further comprising determining a safe and therapeutically effective amount of said at least one anesthetic compound to be administered to each of said individuals lacking said at least one allelic variation, said effective amount corresponding to an individual-specific rate of drug metabolism as determined by phenotypic determinants specific for at least one enzyme known to metabolize said at least one anesthetic compound.

76. The method of claim 74, wherein said step of characterizing a metabolic phenotype comprises a ligand-binding assay specific for said at least one enzyme known to metabolize said at least one anesthetic compound.

77. The method of claim 74, wherein said at least one anesthetic is selected from the group consisting of local and general anesthetics.

78. The method of claim 74, wherein said at least one anesthetic is halothane.

79. The method of claim 76, wherein said ligand-binding assay is selected from the group consisting of immunoassay, enzyme-linked immunosorbent assay (ELISA), microarray formatted immunoassay and microarray formatted ELISA.

80. The method of claim 75, wherein said rate of drug metabolism corresponds to a ratio of phenotypic determinants for at least CYP2E1 enzyme.

81. The method of claim 80, wherein said ratio is selected from the group consisting of concentration ratio, molar ratio, chiral ratio, ratio of area under the curve and signal peak height ratio.

82. The method of claim 76, wherein said ligand-binding assay further provides means to determine phenotypic determinants for at least one of the following enzymes:

NAT2, CYP1A2, NAT1, CYP2A6, CYP2D6, CYP3A4, CYP2C9 and CYP2C19, UGTs, GSTs, and STs.

83. A method of screening a plurality of individuals for participation in a drug treatment trial assessing the therapeutic effect of a candidate anesthetics compound treatment, said method comprising:

a) genotyping each of said individuals to identify individuals lacking at least one allelic variation known to prompt the toxicity of said anesthetics compound; and

b) characterizing a multi-determinant metabolic phenotype of said identified individuals of step a) to determine each individual'"'"'s ability to metabolize said anesthetics compound.

84. The method of claim 83, wherein said at least one anesthetic is selected from the group consisting of local and general anesthetics.

85. The method of claim 83, wherein said at least one anesthetic is halothane.

86. The method of claim 83, wherein said multi-determinant metabolic phenotype is comprised of at least one determinant indicative of an individual'"'"'s metabolic capacity for at least one drug metabolizing enzyme.

87. The method of claim 86, wherein said at least one drug metabolizing enzyme is selected from the group consisting of N-acetyltransferase-1 (NAT1), N-acetyltransferase-2 (NAT2), CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4, CYP2C9, CYP2C19, UGTs, GSTs, and ST.

88. The method of claim 87, wherein said rate of drug metabolism corresponds to a ratio of said phenotypic determinants for said at least one enzyme.

89. The method of claim 88, wherein said ratio is selected from the group consisting of concentration ratio, molar ratio, chiral ratio, ratio of area under the curve and signal peak height ratio.