News Article
Absorbed Faster, Intranasal Exenatide Produces Therapeutic Concentrations Similar to Injectable
ROME (EGMN) - Intranasal administration of exenatide produced therapeutic plasma concentrations similar to those of the current injectable formulation but with faster absorption, according to the results of a study involving 20 patients with type 2 diabetes who were taking at least one other glucose-lowering agent.
The single blind, dose-escalation, placebo-controlled study was funded by Amylin Pharmaceuticals Inc., which manufactures exenatide (Byetta). Because the product is already available in injected form, not all of the usual preliminary analyses were required for the intranasal formulation. The current study, which assessed pharmacokinetics, pharmacodynamics, safety, and tolerability, can be classified as phase 2, Mark Fineman, executive director of clinical pharmacology at Amylin, said in an interview. Mr. Fineman presented his findings as a poster at the annual meeting of the European Association for the Study of Diabetes.
Each study participant initially received a 5-mcg injection of exenatide 30 minutes after receiving an intranasal saline placebo, and then intranasal saline alone on a separate day. Thereafter, 11 patients each received 60, 200, and 600 mcg of intranasal exenatide on separate days (2-8 days apart), while 6 other patients received 600, 800, 1,200, and 1,800 mcg of intranasal exenatide. (Three patients withdrew for non-drug related reasons.) Each dose was delivered with one to three 100-mcL nasal sprays. A standardized meal was given immediately following each exenatide administration. Blood samples were taken before and during the subsequent 8 hours.
The 13 men and 7 women in the intent-to-treat population had a mean age of 55 years, body mass index of 31 kg/m², baseline hemoglobin A
Plasma exenatide concentrations peaked at 15-30 minutes with the intranasal formulation, vs. 2 hours with the subcutaneous injection. "There's an advantage from a mealtime perspective to have this fast absorption," Mr. Fineman noted.
Exenatide exposure increased in a dose-dependent manner from 60 to 1,800 mcg, and therapeutic concentrations of greater than 12 pmol/L were maintained for 3-5 hours in all doses of 600 mcg and higher. Intranasal administration of exenatide at doses of 600 mcg or greater led to an insulin response consistent with first-phase insulin secretion. Insulin secretion was diminished as glucose approached euglycemia.
Near-maximal improvements in postprandial glucose were seen at the 600-mcg dose, and were maintained at all the higher doses as well. Greater postprandial glucose reductions were seen with the 600-mcg dose of intranasal exenatide than with the 5-mcg subcutaneous dose, he pointed out.
"In this fairly simple study, we wanted to find out whether the drug gets in through the nose, and if so, does it work. The answer to both was yes," he said in the interview.
Nausea and vomiting occurred in six and five patients, respectively, at doses of 600 mcg or above. Nausea also occurred in one patient with intranasal saline placebo. Sneezing occurred with intranasal exenatide in two patients and with intranasal placebo in one patient. Overall, intranasal exenatide was generally well-tolerated with no serious adverse events or hypoglycemic events. "I think tolerability will be pretty similar to Byetta," Mr. Fineman said.
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