Population pharmacokinetics of liraglutide, a once-daily human glucagon-like peptide-1 analog, in healthy volunteers and subjects with type 2 diabetes, and comparison to twice-daily exenatide.
The once-daily human glucagon-like peptide-1 (GLP-1) analog, liraglutide, was recently shown to provide improved glycemic control in subjects with type 2 diabetes (T2D) compared with exenatide. The aim of this work is to estimate the population pharmacokinetics of liraglutide and make a comparison to the pharmacokinetic profile of exenatide. Pharmacokinetic data from 5 published studies of subcutaneous and intravenous administration of liraglutide to healthy volunteers (HV) and subjects with T2D were used to develop a population pharmacokinetic model in NONMEM. Exenatide data came from a published study in T2D. Liraglutide pharmacokinetics were adequately described using a 1-compartment model with sequential zero- and first-order absorption. The pharmacokinetic profile of once-daily liraglutide showed considerably smaller peak-to-trough fluctuations compared with twice-daily exenatide. A small difference in the estimates of absorption parameters was found between HV and subjects with T2D but was not clinically relevant. It was concluded that pharmacokinetic profiles estimated by modeling showed that liraglutide has pharmacokinetic properties consistent with once-daily dosing in humans and provides better pharmacokinetic coverage in comparison with twice-daily exenatide. Furthermore, no clinically relevant differences were found in liraglutide pharmacokinetics between HV and subjects with T2D.
Novo Nordisk A/S, Novo Alle, Postbox 1000, DK-2880 Bagsvaerd, Denmark. ellw@novonordisk.com
Estelle
E
Watson
Daniël M
DM
Jonker
Lisbeth V
LV
Jacobsen
Steen H
SH
Ingwersen
D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004334:Drug Administration Schedule; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000069450:Liraglutide; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014688:Venoms / Q000008:administration & dosage / Q000493:pharmacokinetics*
D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide