Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of a Single-Dose of NN2211, a Long-Acting Glucagon-Like Peptide 1 Derivative, in Healthy Male Subjects

• Published in: Diabetes care Vol. 25; no. 8; pp. 1398 - 1404
• Main Authors: ELBRØND, Bodil, JAKOBSEN, Grethe, LARSEN, Søren, AGERSØ, Henrik, JENSEN, Lisbeth Bjerring, ROLAN, Paul, STURIS, Jeppe, HATORP, Vibeke, ZDRAVKOVIC, Milan
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-08-2002
• Subjects: Adolescent; Adult; Analysis; Biological and medical sciences; Blood Glucose; Diabetes; Double-Blind Method; Drug therapy; Glucagon - administration & dosage; Glucagon - adverse effects; Glucagon - analogs & derivatives; Glucagon - blood; Glucagon - pharmacokinetics; Glucagon-Like Peptide 1 - analogs & derivatives; Hormones. Endocrine system; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - pharmacokinetics; Insulin - blood; Liraglutide; Male; Medical sciences; Middle Aged; Peptides; Pharmacokinetics; Pharmacology; Pharmacology. Drug treatments; Denmark; Endocrinopathy; Pharmacokinetic pharmacodynamic relationship; Glucagon; Healthy subject; Secretion; Toxicity; Diabetes mellitus; Glucagon like peptide 1; Chemotherapy; Treatment; Secondary effect; Application method; Pharmacokinetics; Glycemia
• ISSN: 0149-5992; 1935-5548
• DOI: 10.2337/diacare.25.8.1398

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of a Single-Dose of NN2211, a Long-Acting Glucagon-Like Peptide
1 Derivative, in Healthy Male Subjects
Bodil Elbrønd , MD 1 ,
Grethe Jakobsen , MSC 1 ,
Søren Larsen , MSC 1 ,
Henrik Agersø , PHD 1 ,
Lisbeth Bjerring Jensen , PHD 1 ,
Paul Rolan , MD 2 ,
Jeppe Sturis , PHD 1 ,
Vibeke Hatorp , MSC 1 and
Milan Zdravkovic , PHD 1
1 Novo Nordisk A/S, Health Care Development, Bagsvaerd, Denmark
2 Medeval Ltd., Manchester Science Park, Manchester, U.K
Abstract
OBJECTIVE —The primary objective of the present study was to investigate the safety, tolerability, and pharmacokinetics of a single
dose of NN2211, a long-acting glucagon-like peptide 1 (GLP-1) derivative, in healthy male subjects. The secondary objective
was to investigate the pharmacodynamics of NN2211.
RESEARCH DESIGN AND METHODS —In a double-blind, randomized dose, escalation, placebo-controlled study, healthy male subjects were enrolled at eight consecutive
dose levels (1.25, 2.5, 5.0, 10.0, 12.5, 15.0, 17.5, and 20.0 μg/kg) with eight subjects per dose level at a 3:1 active:placebo
randomization. After subcutaneous dosing with NN2211, 48-h pharmacokinetic, and 24-h glucose, insulin and glucagon profiles
were assessed. In addition, three subjects at each dose level were randomly assigned (one placebo/two active) to an intravenous
glucose tolerance test (IVGTT) 9 h after the dose (corresponding to the time to maximal plasma concentration of NN2211).
RESULTS —After subcutaneous administration, the half-life of NN2211 was found to be 11–15 h. Overall, although there were no statistically
significant differences compared with placebo in the area under the curve (0–9 h for insulin or glucagon), there was a borderline-
significant lowering of glucose levels ( P = 0.066). During the IVGTT, there was a statistically significant increase in insulin secretion ( P = 0.0002), but there was no significant effect on glucagon levels. Although no significant effect was observed on glucose
levels during the IVGTT, there was a dose-dependent increase in the glucose disappearance constant. Whereas no serious adverse
events were observed, there was a higher incidence of adverse events after active treatment compared with placebo treatment
(notably headache, dizziness, nausea, and vomiting).
CONCLUSIONS —This study provides evidence that NN2211 has a pharmacokinetic profile consistent with once-daily dosing in humans.
AUC, area under the curve
Cmax, maximal plasma concentration
DPP-IV, dipeptidyl peptidase IV
ECG, electrocardiogram
GLP-1, glucagon-like peptide 1
IVGTT, intravenous glucose tolerance test
Kg, glucose disappearance constant
Footnotes
Address correspondence and reprint requests to Milan Zdravkovic, PhD, Novo Nordisk A/S, Health Care Development, Novo Allé,
2880 Bagsvaerd, Denmark. E-mail: mzd{at}novonordisk.com .
Received for publication 30 October 2001 and accepted in revised form 2 May 2002.
B.E., G.J., S.L., H.A., L.B.J., J.S., V.H., and M.Z. hold stock in Novo Nordisk A/S.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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