The pharmacokinetics of the once-daily human glucagon-like peptide-1 analogue, liraglutide, across 5 trials in healthy subjects and type 2 diabetics after single and multiple dosing
Estelle Watson, Daniël M. Jonker, Steen H. Ingwersen
Biomodelling Department, Novo Nordisk, DK-2880 Bagsværd, Denmark
Objectives: The aim of this study was to investigate the pharmacokinetics (PK) of liraglutide in healthy subjects and in type 2 diabetic patients after a single dose and multiple dosing.
Methods: A population PK model was developed using NONMEM in a stepwise fashion, initially based on a single trial in healthy volunteers (HV). Data from 3 trials in type 2 diabetic (T2D) subjects receiving each a single subcutaneous (sc) dose was then added to the analysis set and the model re-evaluated. Finally, the PK model based on these four intensively sampled trials was applied to a fifth, sparsely sampled phase 2 trial in T2D subjects that were dosed once daily.
Results: The PK of liraglutide in HV was adequately described using a one compartment model with first order elimination and sequential zero-and first-order absorption. The absorption of liraglutide following sc administration was slow, with peak concentrations occurring at 9-12 hours post-dosing. The elimination half-life of liraglutide was estimated to be 13 h, which is longer than the half-life observed after intravenous administration (8.1 h), indicating that slow absorption contributes to the prolonged exposure to liraglutide. In T2D subjects, essentially the same exposure profile was estimated after single sc doses, except for a slightly higher peak concentration due to a difference in absorption kinetics. On the analysis set with single dose data in HV and T2D, V/F was estimated to be 0.16 L/kg (rSE 43%, BSV 47%), and CL/F 0.013 L/hr kg-1 (rSE 4.8%, BSV 37%).The exposure observed after multiple sc doses with sparse sampling did not allow independent estimation of the full PK model, but the data was consistent with simulations based on single dose data.
Conclusions: Liraglutide has a similar exposure in healthy volunteers and type 2 diabetics that is consistent with a once daily dosing regimen. Slow absorption kinetics contributes to the prolonged exposure profile.