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, MD1,
- Grethe Jakobsen, MSC1,
- Søren Larsen, MSC1,
- Henrik Agersø, PHD1,
- Lisbeth Bjerring Jensen, PHD1,
- Paul Rolan, MD2,
- Jeppe Sturis, PHD1,
- Vibeke Hatorp, MSC1 and
- Milan Zdravkovic, PHD1
- 1Novo Nordisk A/S, Health Care Development, Bagsvaerd, Denmark
- 2Medeval Ltd., Manchester Science Park, Manchester, U.K
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
Address correspondence and reprint requests to Milan Zdravkovic, PhD, Novo Nordisk A/S, Health Care Development, Novo Allé, 2880 Bagsvaerd, Denmark. E-mail:.
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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