Methods of using buffered formulations of exendin (9-39)
Provided herein are liquid pharmaceutical formulations comprising exendin (9-39) or a pharmaceutically acceptable salt thereof and a tonicity modifier in a physiologically acceptable buffer having a pH in the range of about 5 to about 6. In some embodiments, the buffered liquid formulation comprises exendin (9-39) or a pharmaceutically acceptable salt thereof in an acetate buffer or a citrate buffer. Methods of treating or preventing hyperinsulinemic hypoglycemia in a subject comprising administering to the subject the buffered liquid formulation are also provided.
1. A method for treating hyperinsulinemic hypoglycemia (HH) in a subject, the method comprising administering to the subject a liquid pharmaceutical formulation comprising exendin (9-39) or a pharmaceutically acceptable salt thereof and a tonicity modifier in a physiologically acceptable buffer having a pH in the range of 5.1 to 6;
wherein the liquid pharmaceutical formulation is formulated for oral, intravenous, buccal, rectal, parenteral, intraperitoneal, intradermal, intramuscular, subcutaneous, or inhalational administration;
wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof does not exhibit detectable aggregation in the pharmaceutical liquid formulation; and
wherein the liquid pharmaceutical formulation has an improved pharmacokinetic profile as compared to a composition comprising the same dose of exendin (9-39) or a pharmaceutical acceptable salt thereof formulated in 0.9% normal saline.
2. The method of claim 1 , wherein the method comprises administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a daily dosage of about 30 mg to 90 mg.
3. The method of claim 2 , wherein the method comprises administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) once per day (QD) or twice per day (BID).
4. The method of any of claim 1 , wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).
5. The method of claim 1 , wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 15 mg, 30 mg, or 45 mg twice daily (BID).
6. The method of claim 1 , wherein the subject has previously had an upper-gastrointestinal procedure.
7. The method of claim 1 , wherein the subject has previously had a bariatric procedure.
8. The method of claim 1 , wherein the physiologically acceptable buffer comprises an acetate buffer or a citrate buffer.
9. The method of claim 1 , wherein the physiologically acceptable buffer comprises sodium acetate or sodium citrate.
10. The method of claim 1 , wherein the physiologically acceptable buffer comprises sodium acetate or sodium citrate at a concentration from about 5 mM to about 30 mM.
11. The method of claim 1 , wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.
12. The method of claim 1 , wherein the physiologically acceptable buffer has a pH in the range of 5.2 to 5.8.
13. The method of claim 12 , wherein the pH is about 5.5.
14. The method of claim 1 , wherein the tonicity modifier comprises mannitol, dextrose, glycerin, lactose, sucrose, or trehalose.
15. The method of claim 14 , wherein the tonicity modifier comprises mannitol.
16. The method of claim 14 , wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.
17. The method of claim 16 , wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.
18. The method of claim 1 , wherein the pharmaceutically acceptable salt of exendin (9-39) is exendin (9-39) acetate or exendin (9-39) trifluoroacetate.
19. The method of claim 1 , wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.
20. The method of claim 19 , wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of at least 15 mg/ml.
21. The method of claim 19 , wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 30 mg/ml.
22. The method of claim 1 , wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 60 mg/ml.
23. The method of claim 1 , formulated for subcutaneous administration.
24. The method of claim 1 , wherein the liquid pharmaceutical formulation exhibits a higher C max for exendin (9-39) than a formulation comprising the same dose of exendin (9-39) or a pharmaceutically acceptable salt thereof formulated in 0.9% normal saline.
25. The method of claim 1 , wherein the liquid pharmaceutical formulation exhibits a higher 12-hour AUC for exendin (9-39) than a formulation comprising the same dose of exendin (9-39) or a pharmaceutically acceptable salt thereof formulated in 0.9% normal saline.
26. The method of claim 1 , wherein the liquid pharmaceutical formulation exhibits a higher trough plasma concentration for exendin (9-39) than a formulation comprising the same dose of exendin (9-39) or a pharmaceutically acceptable salt thereof formulated in 0.9% normal saline.