Comparison pharmacokinetics of two concentrations (0.7% and 1.0%) of Nasulin, an ultra-rapid-acting intranasal insulin formulation.
BACKGROUND
This pharmacokinetic (PK) study was designed to characterize the dose response of two concentrations (0.7% and 1%) of a nasal spray of recombinant regular human insulin in combination with cyclopentadecalactone (CPE-215), a compound that enhances absorption of molecules across mucous membranes (Nasulin, CPEX Pharmaceuticals). Nasulin has been effective in lowering blood glucose in both normal subjects and diabetes patients, and additional dosing options would allow greater titration flexibility.


METHODS
A five-period crossover study of 24 healthy, nonsmoking subjects (ages 18-50, basal metabolic index <33 kg/m(2), weight >70 kg) were studied. Subjects were in a fasted state for 5 h before and 45 min after administration for PK assessment and were then given a meal. Each spray contained 100 microl. Doses tested were 25, 35, 50, 70, and 100 U. Maximum concentration (C(max)) and area under the curve (AUC) were estimated for each dose group. Glucose measurements were also performed.


RESULTS
A dose response (slope of the natural log response versus dose) was demonstrated by baseline-adjusted C(max) of 22, 27, 56, 62, and 84 microU/ml for the 25, 35, 50, 70, and 100 U doses (p < .0001), respectively, and by baseline-adjusted AUC((0-45 min)) values of 491, 592, 1231, 1310, and 1894 microU/ml/min (p < .0001). Glucose AUC((0-45 min)) determinations also demonstrated a pharmacodynamic (PD) dose response.


CONCLUSIONS
Proportional and linear dose responses for both PK and PD parameters were demonstrated for the two concentrations, making multiple doses available for clinical development.
CPEX Pharmaceuticals, Inc, Exeter, New Hampshire 03833 , USA. rstote@cpexpharm.com
Robert
R
Stote
Thomas
T
Marbury
Leon
L
Shi
Michael
M
Miller
Poul
P
Strange
D000281:Administration, Intranasal; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects; D018592:Cross-Over Studies; D003517:Cyclopentanes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D007328:Insulin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D055815:Young Adult
D001786:Blood Glucose; D003517:Cyclopentanes; D007004:Hypoglycemic Agents; D007328:Insulin; C449399:cyclopentenone carboxylic acid