The pharmacodynamics and activity of intranasally administered insulin in healthy male volunteers.

The objective of the study was to assess the bioavailability and absorption dynamics of intranasal insulin (with di-decanoyl-alpha-phosphatidylcholine, DDPC, as absorption enhancer) in two potencies (U200 and U500). Toward this aim, the euglycemic clamp technique combined with somatostatin (100 micrograms/h) was used. Insulin was administered to 12 healthy males: 5 IU intravenously (20-min infusion); 10 IU subcutaneously; 50 IU (U200) and 50 IU, 100 IU, and 150 IU (U500) intranasally. Peak insulin levels (mean +/- SD) were reached at 17.9 +/- 2.6, 77.9 +/- 38.3, 23.3 +/- 5.4, 25.4 +/- 8.4, 26.2 +/- 8.3, and 27.5 +/- 5.8 min, respectively. For the 50 IU dose, peak glucose requirements during the clamp and time to peak were not significantly different for U200 and U500: 548.8 +/- 279.5 vs. 452.4 +/- 232.9 mg/min and 41.3 +/- 16.2 vs. 51.5 +/- 29.9 min, respectively. Compared with intravenous insulin, the bioavailability calculated from the total area under the insulin curve was 13.2% (95% confidence interval 7.9, 21.9) and 8.8% (95% confidence interval 5.6, 13.8), and compared with subcutaneous insulin, the bioavailability was 14.8% (95% confidence interval 8.7, 25.2) and 9.9% (95% confidence interval 6.4, 15.4) for the U200 and U500 preparations, respectively. An apparent nonlinear dose-dependent relation was found for the U500 potency. The within-subject variability of the areas under the curves of plasma insulin after the administration of 100 IU was 43.6% (range 20.7-85.7). In conclusion, this nasal insulin preparation has promising absorption and action profiles in both potencies, which makes it suitable for further exploration of clinical applications.