Pharmacokinetics and pharmacodynamics of intranasal insulin administered to healthy subjects in escalating doses.
BACKGROUND
This exploratory study examined the pharmacokinetics and pharmacodynamics of a Bentley Pharmaceuticals, Inc. (North Hampton, NH) proprietary insulin formulation utilizing CPE-215 technology designed for intranasal administration.


METHODS
Eight fasting healthy volunteers (four men, four women; body mass index, 23.6 +/- 1.7 kg/m2) received up to four doses of intranasal insulin at least 1 week apart. Serum insulin, C-peptide, and plasma glucose were measured in the 4-h period following administration.


RESULTS
At doses of 18.75 IU and above, a rise in serum insulin levels accompanied by a decrease in plasma glucose and serum C-peptide levels was seen. Insulin levels peaked in 10-20 min and remained elevated for approximately 1 h, and the resultant hypoglycaemic effect peaked at 40 min and returned to normal 1.5-2 h post-dosing. At 25 IU (n = 11 doses; eight subjects with three replicates), there was a mean fall in plasma glucose of 20.49%; a greater fall in plasma glucose was seen with higher insulin doses. In addition, mean peak insulin levels increased with dose escalation. For the 25 IU dose (a single 90-microL spray), the maximum measured insulin concentration was 19.52 +/- 9.28 mIU/L, and the area under the concentration-time curve from 0 to 4 h was 19.06 +/- 5.56 mIU/L/h. Three subjects with repeated 25 IU doses demonstrated similarly reproducible peaks for maximum measured insulin concentration and for plasma glucose reductions. As seen with other insulin studies, the inter-individual responsiveness to insulin was variable.


CONCLUSIONS
This intranasal formulation was generally well tolerated and demonstrated rapid onset of action and appropriate duration of action for the potential use in controlling postprandial hyperglycaemia.
Leary
Andrew C
AC
Department of Pharmacology and Therapeutics, National University of Ireland; and Shandon Clinic, Cork, Ireland. andrew.leary@shandonclinic.ie
Stote
Robert M
RM
Breedt
H J
HJ
O'Brien
Jackie
J
Buckley
Brendan
B
D000281:Administration, Intranasal; D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism*; D002096:C-Peptide / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D012016:Reference Values
D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin