METHODS AND COMPOSITIONS FOR ASSESSING AND TREATING EMETOGENIC DRUG-RELATED NAUSEA

• US 20190317114A1
• Filed: 10/09/2017
• Published: 10/17/2019
• Est. Priority Date: 10/10/2016
• Status: Active Grant

• Current Assignee: Lankenau Institute for Medical Research
• Original Assignee: Lankenau Institute for Medical Research
• Inventors: Wallon, Margaretha
• Granted Patent: US 11,761,949 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: G01N 33/49 Blood chemical methods for determining blood cell populations G01N33/5094; chemical analysis of blood groups or blood types G01N33/80
• CPC Class Codes: G01N 33/50 Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing measuring or testing processes involving enzymes or microorganisms, compositions or test papers therefor; processes for forming such compositions, condition responsive control in microbiological or enzymological processes C12Q
• CPC Class Codes: G01N 33/5091 for testing the pathological state of an organism
• CPC Class Codes: G01N 33/52 Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements immunological elements G01N33/54386; involving labelled immunochemicals G01N33/58; for haemoglobin or occult blood G01N33/72
• CPC Class Codes: G01N 33/5306 Improving reaction conditions, e.g. reduction of non-specific binding, promotion of specific binding
• CPC Class Codes: G01N 33/80 involving blood groups or blood types or red blood cells white blood cells G01N33/56972

Abstract

A method for assessing susceptibility to nausea of a patient comprises assessing the GSH recycling dependent antioxidant activity of the patient'"'"'s blood cells prior to receiving an emetogenic agent, e.g., a cytostatic agent or a surgical anesthetic.

Claims

1. A method for assessing susceptibility to nausea comprising assaying a biological sample containing red blood cells (RBC) for glutathione (GSH) recycling dependent antioxidant activity of the RBC as an indicator of oxidative stress, said sample obtained from a mammalian subject prior to administration of an emetogenic agent, wherein a high level of oxidative stress is predictive of increased susceptibility to nausea.

3. The method according to claim 1, comprising contacting the sample with hydroxyethyldisulfide (HEDS);

quantifying the amount of ß

-mercaptoethanol (ME) released by the sample treated with the HEDS and spectrophotometrically measuring absorbance readings of ME;

converting absorbance readings into ME concentrations;

normalizing ME concentrations to total RBC count at the time of blood draw;

measuring the GSH recycling dependent antioxidant activity of intact RBC in said sample, and diagnosing the subject as likely to experience emetogenic agent-related moderate to severe nausea when the sample indicates a low GSH recycling capacity.

4. The method according to claim 3, wherein a low GSH recycling capacity is less than a mean+2×

Standard deviation of about 1.0.

5. The method according to claim 1, wherein

(a) said subject has a cancer requiring treatment with an emetogenic cytostatic agent or is undergoing a surgical procedure requiring an emetogenic general anesthesia agent;

or

(b) the nausea is chemotherapeutic induced nausea-vomiting (CINV).

7. The method according to claim 1, further comprising:

predicting delayed nausea for a subject with cancer during treatment with a highly or moderately emetogenic cytostatic chemotherapeutic drug when the sample indicates a low GSH recycling activity;

or

predicting delayed nausea for a subject undergoing surgery requiring an emetogenic general anesthetic agent when the sample indicates a low GSH recycling capacity.

9. The method according to claim 1, further comprising:

optimizing the subject'"'"'s treatment by treating the subject with an antiemetic drug prior to, during, or after administration of said emetogenic agent, when the subject'"'"'s RBCs demonstrate a low glutathione recycling activity;

or

optimizing the subject'"'"'s treatment by treating the subject having cancer with an antiemetic drug prior to, during, or after administration of a highly or moderately emetogenic chemotherapeutic drug, when the subject'"'"'s RBCs demonstrate a low GSH recycling activity;

or

optimizing the subject'"'"'s treatment by treating the subject having cancer with a selected antiemetic drug regimen drugs prior to, during or after administration of a low or moderately emetogenic chemotherapeutic drug, or eliminating the antiemetic regimen, when the subject'"'"'s RBCs demonstrate a high GSH recycling activity;

or

optimizing the subject'"'"'s treatment by treating the subject having cancer when the subject'"'"'s RBCs demonstrate a high glutathione recycling dependent antioxidant activity with an antiemetic drug regimen comprising 2 or less different antiemetic drugs prior to, during, administration of a moderately emetogenic or low emetogenic chemotherapeutic;

or

optimizing the subject'"'"'s treatment by treating the subject undergoing surgery with an antiemetic drug regimen comprising 3 or more different antiemetic drugs prior to, during or after administration of a highly or moderately emetogenic anesthetic agent, when the subject'"'"'s RBCs demonstrate a low GSH recycling dependent antioxidant activity;

or

optimizing the subject'"'"'s treatment by treating the subject undergoing surgery with either an antiemetic drug regimen of 0, 1 or 2 different antiemetic drugs prior to, during, or after administration of a moderately emetogenic or low emetogenic anesthetic agent when the subject'"'"'s RBCs demonstrate a high glutathione recycling dependent antioxidant activity.

15. A method for treating a subject with cancer comprising

a. assaying a biological sample containing RBC obtained from a mammalian subject prior to administration of an emetogenic chemotherapeutic drug with the method of claim 1;

b. determining the level of oxidative stress in said sample, wherein a high level of oxidative stress is predictive of susceptibility to nausea; and

c. administering to said subject a selected therapeutic regimen depending upon the level of oxidative stress in the sample, wherein the regimen is selected from;

(i) a highly or moderately emetogenic chemotherapeutic with an antiemetic drug regimen of two or less antiemetic drugs;

(ii) a highly or moderately emetogenic chemotherapeutic with no antiemetic drug;

(iii) a low emetogenic chemotherapeutic with an antiemetic drug regimen of two or less antiemetic drugs;

(iv) a low emetogenic chemotherapeutic with no antiemetic drug;

or

(v) a full regimen of at least 3 antiemetic drugs with any emetogenic chemotherapeutic drug.

17. The method according to claim 15, comprising selecting regimen (i) to (iv) when the subject'"'"'s RBCs demonstrate a high GSH recycling dependent antioxidant activity.

18. A method of reducing the toxicity of drug regimens comprising:

a. assaying a biological sample containing RBC for a level of oxidative stress by the method of claim 1; and

b. reducing or eliminating the number of antiemetic drugs administered to the subject before, during or after administration of an emetogenic agent depending upon the level of oxidative stress.

19. The method according to claim 18, wherein the assaying is performed by contacting the sample with a reagent that permits an assessment of the glutathione (GSH) recycling dependent antioxidant activity of the RBC in the sample as an indicator of oxidative stress.

20. The method according to claim 18, comprising selecting the appropriate reduction or elimination of the number of antiemetic drugs in the drug regimen, when the subject'"'"'s RBCs demonstrate a high GSH recycling dependent antioxidant activity.

21. The method according to claim 18, wherein the subject receiving the drug regimen is a subject with cancer, and the emetogenic agent is a cytostatic agent, or wherein the subject is undergoing a surgical procedure requiring an emetogenic general anesthesia agent.

23. A method of managing a chemotherapeutic treatment in a subject having cancer, said method comprising:

(a) determining whether said subject has a low oxidative level in a blood sample taken prior to administration of an emetogenic cytostatic chemotherapeutic agent, using the method of claim 1; and

(b) managing a future therapeutic regimen for said subject based on said determining step (a).

24. A method of managing nausea in a surgical subject, said method comprising:

(a) determining the level of oxidative stress level in a blood sample taken prior to administration of an emetogenic anesthesia agent, using the method of claim 1; and

(b) managing a future therapeutic regimen for said subject based on said determining step (a).

30. A method for recommending a modification to a drug regimen prior to treatment of a subject with an emetogenic cytostatic or anesthetic agent, the method comprising:

(a) identifying a subject who is prescribed therapy with an emetogenic agent;

(b) determining a prescribed drug regimen consisting of the emetogenic agent and multiple antiemetic drugs;

(c) measuring the level of oxidative stress in a sample from the subject with the method of claim 1;

(d) identifying the subject as nausea predisposed when administered highly/moderate emetogenic therapy if the GSH recycling activity is less than a predetermined level, and as nausea resistant to said therapy if the GSH recycling activity is greater than the predetermined level; and

either

(i) recommending a modification to the drug regimen if the subject is identified as nausea predisposed, wherein the modification comprises a discontinuation of the emetogenic agent or a replacement of the emetogenic agent with a new regimen comprising co-administering three or more antiemetic drugs with the emetogenic agent;

or

(ii) recommending a modification to the drug regimen if the subject is identified as nausea resistant, wherein the modification comprises comprising administering the emetogenic agent with a reduction in the number of antiemetic drugs or with no antiemetic drug.

2. (canceled)

6. (canceled)

8. (canceled)

10-14. -14. (canceled)

16. (canceled)

25. (canceled)

26. A method of selecting a population for individualized therapeutic regimen comprising classifying a patient for the likelihood of developing nausea into a low likelihood or high likelihood category prior to selecting or administering a drug regimen comprising a high or moderately emetogenic agent with an antiemetic drug regimen comprising one to three antiemetic drugs or with an antiemetic drug regiment comprising greater than three antiemetic drugs.

22. The method according to claim 26 comprising:

(a) providing at least one reagent capable of interacting with red blood cells and generating an indicator of oxidative stress in a blood sample of a patient obtained prior to treatment with an emetogenic agent;

(b) detecting in said sample from said patient the level of oxidative stress by providing a measurement of GSH recycling dependent antioxidant activity in the RBC wherein a high or increased level of oxidative stress is predictive of susceptibility to nausea;

(c) classifying the sample of said patient from the outcome of the comparison in step (b) into one of at least two classifications of low or high oxidative stress levels to permit selection of a drug regimen, wherein the drug regimen comprises the administration of two or less than two antiemetic drugs, or no antiemetic drug or three or more antiemetic drugs, before, during or after administration of

(i) a high to moderately emetogenic cytostatic chemotherapeutic agent, where the subject has cancer;

(ii) a low emetogenic cytostatic chemotherapeutic, where the subject has cancer;

or

(iii) an emetogenic anesthesia agent, wherein the subject is undergoing a surgical procedure.

27. (canceled)

28. A system or kit for determining whether a subject has a high or low nausea response to an emetogenic agent, said system or kit comprising:

(a) assay reagents for measuring oxidative stress in the RBC of a whole blood sample taken from the subject prior to treatment with the emetogenic agent; and

(b) a nausea phenotype determination element for determining whether said subject has a is predisposed to nausea or resistant to nausea, the phenotype determination element comprising a reference profile for an oxidative level of RBC, wherein the phenotype determination element is obtained from a sample from one of more patients with a nausea predisposed phenotype or a nausea resistant phenotype, wherein a high level of oxidative stress is predictive of susceptibility to nausea.

29. (canceled)

31. (canceled)