TREATMENT OF POST-BARIATRIC HYPOGLYCEMIA WITH EXENDIN (9-39)

• US 20180117122A1
• Filed: 05/23/2016
• Published: 05/03/2018
• Est. Priority Date: 05/22/2015
• Status: Active Grant

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: The BOT of The Leland Stanford Junior University
• Inventors: McLaughlin, Tracey L., Craig, Colleen M.
• Granted Patent: US 10,639,354 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48

Abstract

Compositions and methods for treating hyperinsulinemic hypoglycemia, such as hyperinsulinemic hypoglycemia after bariatric surgery, are provided. In some embodiments, an effective amount of the glucagon-like peptide-1 receptor antagonist exendin(9-39) is subcutaneously administered twice per day.

Claims

1. A method for treating or preventing hyperinsulinemic hypoglycemia in a patient who has previously had bariatric surgery, the method comprising subcutaneous administration of a composition comprising a therapeutically effective amount of exendin(9-39) twice-per-day (BID), wherein the therapeutically effective amount is in the range of 10-30 mg exendin(9-39).

2. The method of claim 1, wherein the therapeutically effective amount of exendin(9-39) administered twice-per-day is selected from a dosage in the range of 10-20 mg, a dosage in the range of 10-15 mg, a dosage of 10 mg, a dosage of 15 mg, and a dosage of 20 mg.

5. The method of claim 1, wherein the composition is a solution or suspension that comprises exendin(9-39) at a concentration range selected from 4-20 mg/ml, 10-20 mg/ml, 8-16 mg/ml, and 13-16 mg/ml.

9. The method of claim 1, wherein the composition is administered in a single injection with an injectate volume of 0.5 ml to 1 ml.

10. The method of claim 1, wherein administration results in a steady state plasma exendin(9-39) concentration of at least 100 ng/ml as measured by liquid chromatograph-mass spectrometry.

11. The method of claim 2, wherein each of the twice-per-day administrations result in a Cmax of 100 ng/ml.

12. The method of claim 2, further comprising administering a first daily administration is in the morning and a second daily administration is in the evening, and wherein the first daily administration comprising a morning injectate, the second daily administration comprises an evening injectate, and the second daily administration is at least 8 hours after the first daily administration.

13. The method of claim 12, wherein the first daily administration is administered at a first time selected from before the morning meal, at least 1 hour before the morning meal, 60 to 90 minutes before the morning meal, and during a first period from one hour before the morning meal to one hour after the morning meal.

16. The method of any of claim 12, wherein the second daily administration is administered at a second time selected from 60 to 90 minutes before the evening meal, within two hours of bedtime, during a second period from after the evening meal and to before bedtime, and from 9 to 15 hours after the morning administration.

20. The method of claim 2, wherein the amount of exendin(9-39) in the evening injectate is greater than the amount of exendin(9-39) in the morning injectate.

21. The method of claim 20, wherein the amount of exendin(9-39) in the evening injectate is 5 mg-10 mg greater than the amount of exendin(9-39) in the morning injectate.

22. The method of claim 21, wherein the amount of exendin(9-39) in the morning injectate is selected from 10 mg, 15 mg, and 20 mg.

23. The method of any claim 20, wherein a concentration of exendin(9-39) in the morning injectate is unequal to a concentration of exendin(9-39) in the evening injectate.

24. The method of claim 23 wherein the concentration of exendin(9-39) in the morning injectate is higher than the concentration of exendin(9-39) in the evening injectate.

25. The method of claim 20, wherein a Tmax of the exendin(9-39) after the second daily administration is longer than a Tmax of the exendin(9-39) after the first daily administration.

26. The method of claim 25, wherein the concentration of exendin(9-39) in the morning injectate is selected from 4-20 mg/ml, 10-20 mg/ml, 8-16 mg/ml, and 13-16 mg/ml.

27. The method of claim 25, wherein the concentration of exendin(9-39) in the evening injectate is selected from 4-20 mg/ml, 10-20 mg/ml, 8-16 mg/ml, and 13-16 mg/ml.

29. The method of claim 1 wherein subcutaneous administration twice-per-day comprises administering a morning injectate and an evening injectate, and the amount of exendin(9-39) administered is the same in the morning and evening injectates and the concentration of exendin(9-39) is greater in the evening injectate compared to the morning injectate.

30. The method of claim 29 wherein the concentration of exendin(9-39) in morning injectate is 15 mg/ml and the concentration of exendin(9-39) in the evening injectate is 20 mg/ml.

31. The method of claim 1, wherein the bariatric surgery is Roux-en-Y gastric bypass surgery.

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