Henrik Agersø1, Paolo Vicini. 1. Department of Pharmacokinetics, Novo Nordisk A/S, Maaloev, Denmark. henrik.agersoe@ferring.com
Abstract
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. DESIGN: 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.
RCT Entities:
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. DESIGN: 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.
Authors: Hui Min Chan; Ritesh Jain; Bo Ahrén; Giovanni Pacini; David Z D'Argenio Journal: Am J Physiol Regul Integr Comp Physiol Date: 2011-02-09 Impact factor: 3.619