Pharmacodynamics of NN2211, a novel long acting GLP-1 derivative.
OBJECTIVE
To evaluate the effects of NN2211, a GLP-1 derivative, on glucose and insulin homeostasis in healthy volunteers by use of a nonlinear mixed-effects modeling approach.


METHODS
NN2211 is a GLP-1 derivative intended for the treatment of type 2 diabetes. In the present study, eight dose levels of NN2211 were tested in healthy human volunteers. Since NN2211 is only intended to have an effect when glucose levels are above baseline (thus limiting the risk of hypoglycaemia), no effects would be expected in healthy volunteers. In order to demonstrate effect in a phase 1 study including only healthy subjects, a glucose dose was administered i.v. 9 h after NN2211 dosing; the insulin response would then be expected to be improved (higher) in the subjects dosed with NN2211.


METHODS
In the present work, the pharmacodynamic glucose and insulin response was modeled by fitting glucose and insulin data simultaneously with a nonlinear model incorporating known carbohydrate regulation mechanisms. After an initial model-building phase, the first-order approximation to the likelihood available in NONMEM was used to model the data. Placebo-dosed subjects were included in the analysis.


RESULTS
It was possible to satisfactorily fit both insulin and glucose data simultaneously. The analysis demonstrated a dose proportional effect of NN2211 on the parameters controlling beta cell insulin secretion.
Agersø
Henrik
H
Department of Pharmacokinetics, Novo Nordisk A/S, Maaloev, Denmark. henrik.agersoe@ferring.com
Vicini
Paolo
P
D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000502:physiology; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005934:Glucagon / Q000031:analogs & derivatives* / Q000097:blood* / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D006801:Humans; D007328:Insulin / Q000097:blood; D000069450:Liraglutide; D008297:Male; D017711:Nonlinear Dynamics; D010446:Peptide Fragments / Q000097:blood* / Q000494:pharmacology*; D011498:Protein Precursors / Q000097:blood* / Q000494:pharmacology*
D001786:Blood Glucose; D003692:Delayed-Action Preparations; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon