2007 - København - Denmark

PAGE 2007: Applications- Endocrine
Daniel Jonker

Pharmacokinetic modelling of the once-daily human glucagon-like peptide-1 analogue, liraglutide, in healthy volunteers and comparison to exenatide

Daniël M. Jonker, Estelle Watson, Anders Dyhr Toft, Peter Kristensen, Lotte Bjerre Knudsen, Steen H. Ingwersen

Novo Nordisk A/S, Bagsværd, Denmark

Objectives: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has been shown to stimulate insulin secretion in a glucose-dependent manner, to inhibit glucagon secretion and to delay gastric emptying. These are promising properties for treatment of type 2 diabetes. Liraglutide is a long-acting human GLP-1 analogue that was designed to be eliminated considerably slower than the natural hormone. The aim of this modelling was to develop a pharmacokinetic model on available data on liraglutide and exenatide in man, and thereby compare their pharmacokinetic properties.

Methods: The pharmacokinetics of liraglutide were studied in 72 healthy male subjects using a dose escalation design. Each subject received a single sc injection of 1.25 up to 20 ug/kg liraglutide or vehicle and 22 venous blood samples were collected up to 48 hours after dosing. A population-based modelling approach was taken to describe the time course of liraglutide concentrations and its between-subject variability (BSV) using NONMEM V. During model building, goodness-of-fit was assessed by the objective function value and a range of graphical procedures. The estimates from the final model were used to generate a predicted PK profile for once daily sc dosing. Similarly, a PK profile for twice daily sc dosing of exenatide was generated from literature data.

Results: The absorption of liraglutide following subcutaneous (sc) administration was slow, with peak concentrations occurring at 9-12 hours post-dosing. Liraglutide absorption was adequately described by a dose proportional zero order process and a subsequent first order process. A one-compartment model with a central volume amounting to 0.086 L/kg (rSE 11%, BSV 33%) was estimated, showing that after absorption, liraglutide is mainly confined to the central circulation. Clearance was independent of dose and was estimated to be 0.0060 L/hr kg-1 (rSE 6.8%, BSV 13%). The mean elimination half-life after sc dosing was 13 hr (by noncompartmental analysis). The absolute bioavailability was found to be 51% (rSE 8%, BSV 30%).

Conclusions: The model and data demonstrate suitable pharmacokinetic properties for 24h-coverage with once daily sc administration of liraglutide. In addition, the PK profile of once daily liraglutide was found to have a lower peak to trough variation than that of twice-daily exenatide.

Reference: PAGE 16 (2007) Abstr 1152 [www.page-meeting.org/?abstract=1152]
Poster: Applications- Endocrine