METHODS FOR TREATING TESTOSTERONE DEFICIENCY IN MEN AND METHODS FOR PRECISE DOSING OF UGT2B17 SUBSTRATE DRUGS

• US 20190307773A1
• Filed: 04/10/2019
• Published: 10/10/2019
• Est. Priority Date: 04/10/2018
• Status: Active Grant

• Current Assignee: University of Washington
• Original Assignee: University of Washington
• Inventors: Prasad, Bhagwat, Basit, Abdul, Zhang, Haeyoung, Amory, John K.
• Granted Patent: US 11,131,677 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/4365 the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5685 having an oxo group in position 17, e.g. androsterone
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 5/26 Androgens
• CPC Class Codes: C12Y 204/01017 Glucuronosyltransferase (2.4.1.17)
• CPC Class Codes: G01N 2333/91102 with definite EC number (2.4.1.-)
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/573 for enzymes or isoenzymes
• CPC Class Codes: G01N 33/743 Steroid hormones

Abstract

Treatment of testosterone deficiency in men by a precision medicine approach using a biomarker of activity of UGT2B17 that is involved in testosterone urinary elimination. By inhibiting UGT2B17, alone or in combination with administration of testosterone, testosterone deficiency in men can be treatable. Further, a method of dose selection for precise dosing of UGT2B17 substrate drugs is provided. Additionally, methods for safe dosing of pharmaceutical agents that undergo UGT2B17-mediated acyl glucuronidation are provided.

Claims

1. A method for treating testosterone deficiency in a subject, comprising the steps of:

obtaining a sample from a subject suspected of having testosterone deficiency;

determining the presence in the sample of one or more biomarkers of UGT2B17 activity;

identifying an effective therapeutic amount of one or more agents for treating testosterone deficiency; and

administering the effective therapeutic amount of the agent to treat testosterone deficiency in the subject in need thereof.

2. The method of claim 1, wherein the one or more biomarkers of UGT2B17 activity is a normalized testosterone glucuronide (normalized TG).

3. The method of claim 2, wherein the normalized TG is a ratio of concentration of testosterone glucuronide (TG) to concentration of aldosterone glucuronide (AG), a ratio of concentration of testosterone glucuronide (TG) to concentration of etiocholanolone glucuronide (EG), a ratio of concentration of testosterone glucuronide (TG) to concentration of testosterone sulfate (TS), a ratio of concentration of testosterone glucuronide (TG) to concentration of hydroxyl-testosterone, or a ratio of concentration of testosterone glucuronide TG to concentration of epitestosterone glucuronide (epiT).

4. The method of claim 1, wherein the sample is blood, urine, plasma, or serum.

5. The method of claim 1, wherein the determining the presence of one or more biomarkers of UGT2B17 activity in the sample is done by LC/MS.

6. The method of claim 1, wherein the one or more agents for treating testosterone deficiency comprises testosterone.

7. The method of claim 6, wherein the testosterone is formulated for gastroretentive dosage.

8. The method of claim 1, wherein the one or more agents for treating testosterone deficiency comprises an inhibitor of UGT2B17.

9. The method of claim 8, wherein the inhibitor of UGT2B17 comprises a nonsteroidal anti-inflammatory drug (NSAID).

10. The method of claim 9, wherein the NSAID is ibuprofen, diclofenac, or a combination thereof.

11. The method of claim 8, wherein the inhibitor of UGT2B17 is imatinib.

12. The method of claim 1, wherein the one or more agents for treating testosterone deficiency is administered orally.

13. A method for treating a subject with a pharmaceutical agent that is metabolized by UGT2B17-dependent acyl glucuronidation, comprising the steps of:

obtaining a sample from a subject;

determining the presence of one or more biomarkers of UGT2B17 activity in the sample;

identifying an effective therapeutic amount of a pharmaceutical agent that is metabolized by UGT2B17-dependent acyl glucuronidation; and

administering the effective therapeutic amount of the pharmaceutical agent to the subject in need thereof.

14. The method of claim 13, wherein the pharmaceutical agent is vorinostat, exemestane, or clopidogrel.

15. The method of claim 13, wherein the sample is blood, urine, plasma, or serum.

16. The method of claim 13, wherein the determining the presence of one or more biomarkers of UGT2B17 activity in the sample is done by LC/MS.

17. The method of claim 13, wherein the one or more biomarkers of UGT2B17 activity is a normalized testosterone glucuronide (normalized TG).

18. The method of claim 13, wherein the normalized TG is a ratio of concentration of testosterone glucuronide (TG) to concentration of aldosterone glucuronide (AG), a ratio of concentration of testosterone glucuronide (TG) to concentration of etiocholanolone glucuronide (EG), a ratio of concentration of testosterone glucuronide (TG) to concentration of testosterone sulfate (TS), a ratio of concentration of testosterone glucuronide (TG) to concentration of hydroxyl-testosterone, or a ratio of concentration of testosterone glucuronide TG to concentration of epitestosterone glucuronide (epiT).

19. The method of claim 13, wherein the effective therapeutic amount is an amount that does not result in hepatotoxicity caused by UGT2B17 mediated acyl-glucuronidation in the subject.

20. A method for testing an individual for testosterone doping, the method comprising:

(a) obtaining a biological sample from an individual subject to testosterone doping testing;

(b) determining a ratio of testosterone glucuronide (TG) to aldosterone glucuronide (AG) in the biological sample; and

(c) comparing the ratio of testosterone glucuronide (TG) to aldosterone glucuronide (AG) in the sample with that from a retention sample.